• Open access
  • Published: 17 October 2022

Children with a rare congenital genetic disorder: a systematic review of parent experiences

  • Charlotte von der Lippe   ORCID: orcid.org/0000-0003-3176-0160 1 ,
  • Ingrid Neteland 1 &
  • Kristin Billaud Feragen 1  

Orphanet Journal of Rare Diseases volume  17 , Article number:  375 ( 2022 ) Cite this article

4608 Accesses

12 Citations

3 Altmetric

Metrics details

Caring for a child with a chronic disease may be demanding and stressful. When a child has a rare condition, the impact of care on parents is amplified due to the rarity of the diagnosis. In order to address the lack of generalized and synthesized knowledge regarding parents’ experiences of having a child with a rare genetic disorder, and give a holistic picture of these experiences, a systematic review of the available qualitative research was conducted.

We performed a systematic review, including qualitative studies on parents of children with rare genetic disorders, published between 2000 and 2020.

The review included 33 qualitative studies. Findings were synthesized and categorized according to three main themes: Parents’ experiences with health care, Responsibilities and challenges, and Factors promoting positive experiences in parents. The findings demonstrate that parents of children with rare genetic disorders share many common challenges, despite evident differences across conditions.

Coordinated care, and a more holistic approach in the follow up of children with rare genetic disorders is needed. International collaboration on research, diagnostics, producing scientific correct and understandable information available for health care professionals and lay people should be prioritized.

Introduction

Rare disorders are medical conditions that affect less than 1:2000 individuals or fewer [ 1 ]. In the USA, a disease is considered rare if it affects less than 200, 000 (~ 1:1600) individuals [ 2 ]. Most rare disorders are associated with a genetic cause [ 3 ].

Although rare disorders are rare by definition, it has been estimated that a rare disorder affects as many as one in 16 people [ 4 ]. Rare disorders are often chronic, with various degree of physical and psychological consequences [ 5 , 6 ] . Many rare disorders are congenital and identifiable at birth. For a few rare disorders, treatment may be available [ 7 ], however, for most there is only, if any, symptomatic treatment.

Caring for a child with a chronic disease may be demanding and stressful [ 8 , 9 ], and caregivers of children with health problems have a greater risk of having health problems than those of healthy children [ 10 ]. When a child has a rare condition, care demands may be complicated and possibly amplified because of the rarity of the condition, and parents of a child with a rare diagnosis may therefore experience increased physical and emotional stress [ 11 , 12 , 13 ]. However, parents of children with chronic diseases may also experience positive aspects of parenting, such as increased personal strength and greater appreciation for life [ 14 ].

There are between 6000 and 8000 rare diseases, and it has been estimated that rare conditions may affect as many as 30 million Europeans and 25 million North Americans [ 15 , 16 ]. Hence, many children and their families across the world have to live and cope with the medical, psychological, and social consequences of the rare condition. Due to a low prevalence of each rare disorder, knowledge about most rare disorders is sparse both in society and among health care professionals. Consequences of the lack of knowledge about rare disorders may lead to diagnostic mistakes, delays in diagnosis, and lack of information of high quality [ 17 , 18 , 19 ].

Increased awareness of rare disorders throughout society, and within the health care system, is one suggested action to improve the situation of people with rare disorders [ 20 , 21 ]. With 6000–8000 different rare conditions, the understanding of common experiences that may be present across conditions can be difficult to assess. Therefore, one way to increase knowledge, is to summarize research investigating psychological and social experiences of parents of children with rare disorders across conditions. A synthesis of qualitative studies may benefit from the depth of understanding uncovered by each qualitative inquiry, while also identifying shared experiences identified across studies, and their consequences in everyday life, which may shed light on unmet needs that require coordinated societal responses.

Qualitative methodology [ 22 ] is ideally suited for investigating the psychological, emotional, and social specificities of being the parent of a child with a rare genetic disorder, in order to gain deeper insight into people’s experiences and seeking to understand the meaning or nature of these experiences. Nevertheless, there is a lack of qualitative research exploring parents’ experiences of having a child with a rare genetic disorder, and whether these parents face challenges that are qualitatively different from those experienced by parents of children with more well-known medical conditions. Further, few papers include several different diagnoses in the same study, so that similarities and differences across conditions can be investigated from a psychological perspective, and last, a lack of literature reviews summarize shared experiences of parents of children with a rare genetic disorder.

In order to address the lack of generalized and synthesized knowledge regarding parents’ experiences of having a child with a rare genetic disorder, we conducted a systematic review of the available qualitative research on this population, in order to provide a holistic picture of common experiences across different diagnoses.

The aims of this systematic review were:

To provide an overview of parents’ experiences of having a child with a rare genetic disorder, and explore the psychosocial consequence of these experiences.

To address the overarching question: What experiences do parents of children with rare genetic disorders share?

Materials and methods

Inclusion and exclusion criteria.

A systematic review of the qualitative literature was performed, following the PRISMA statement [ 23 ]. A flow chart of the number of identified and selected articles can be found in Fig.  1 . All original, peer-reviewed articles published in English, addressing parents’ or primary caregivers’ experiences of having a child with a rare congenital genetic condition, based on qualitative or quantitative methodology, and published from January 2000 until November 2020 were included in the search. Quantitative articles were included in the search in order to get an overview also of the quantitative literature of the topic. The quantitative articles were not included in the qualitative synthesis.

figure 1

Flowchart of identified and selected articles

Case studies were excluded. Studies on rare cancers, rare rheumatologic disorders, or rare acquired disorders were excluded, as many of these disorders do not have a clear genetic cause. Studies focusing mainly on the diagnostic process or with a focus on the use of internet were excluded. Reports, oral presentations or abstracts from posters were excluded.

Search strategy

The PROSPERO International prospective register of systematic reviews was searched to be sure a similar study was not started, and a protocol for this study was published (Prospero CRD42018111129).

The search strategy was developed in cooperation with a specialist librarian. We searched the following electronic databases to identify relevant studies, number of hits in parentheses: Ovid Medline (668), APA PsycInfo [ 70 ], Web of Science (163). Date of search was December 3rd, 2020. Total number of hits was 901. Number of hits after removal of duplicates was 793. We used the search words: rare, orphan, diseases, disorder*, diagnosis*, condition, parents, fathers, mothers, single parent, single-parents family, maternal behavior, paternal behavior, parent–child relations, father-child relations, mother–child relations, parenting, child rearing, caregivers, professional family relations, family, family relations, family conflict, parent*, caregiver*, caregiving, carer, carers, mother, father, maternal*, paternal*,family*, families, experienc*, lived experienc*, cope*, coping, parental characteristics, parental attitudes, parental role, parenting skills, parenting style, childrearing practices, child discipline, parent child communication, parent child relations, childrearing attitudes, parental involvement, including MeSH terms.

The search was restricted to English language, key words, titles and abstracts, and publication time was restricted to January 2000–November 2020.

Selection of included papers

Search results were merged using EndNoteX9 and duplicates were removed. Three independent reviewers examined the titles and abstracts, and selected papers for full-text reading. All three reviewers read full-text of selected papers, and papers were included in the study according to the agreed criteria (Additional file 1 : Appendix I). Questions used to include or exclude publications after full-text reading were (1) Is the study empirical and in English? (2) Is the child’s diagnosis rare and genetic? (3) Is the study about experiences of being parent to a child (any age)? (4) Is the study qualitative or quantitative?, and (5) Does the study follow standards for reporting qualitative research [ 24 ].

If the answers to questions 1- 3, and 5, were yes, and the study was qualitative, we included the study in the synthesis. Any potential disagreements between the authors were resolved through discussion.

Data extraction

All three co-authors collected data regarding citation/contact details, methods, design, participants, setting/context and results/findings (Additional file 2 : Appendix II).

Data synthesis

Qualitative research is specific to a particular context, time and group of participants, and caution is therefore needed when generalizing results. Having this in mind, it is however possible to extract results from different qualitative studies, and synthesize findings. Several methods for synthesizing qualitative data have been recommended [ 25 ], and thematic synthesis [ 26 ] was employed in the present review. All findings were extracted from the included studies’ result sections. Following extraction, the text was coded, and codes were grouped into meaningful categories, so called descriptive themes. CvdL and IN independently synthesized the data extracted, before discussing themes. Subsequently, KBF, familiar with all included papers, reviewed the themes before going through the codes to check whether they had been included in the themes. All three authors agreed on the final themes. The synthesis presents the overall findings in analytical themes and subthemes, and as presented by the authors in the publication’s result section. Rare genetic disorders are referred to as ‘rare disorders’ in the Results and Discussion.

In total, 33 qualitative articles were included, representing a wide range of rare diagnoses and conditions. An overview with details of the included articles can be found in Table 1 .

The findings demonstrate that parents shared a range of common experiences despite the uniqueness of their child’s condition. Three main themes were identified: (1) Parents’ experiences with health care, (2) Responsibilities and challenges, and (3) Factors promoting positive experiences in parents. All main themes included subthemes, which will be subsequently described. An overview of themes and subthemes in relation to all included studies can be found in Table 2 .

Theme 1: Parents’ experiences with health care

All studies except three explored parents’ experiences with health care services in charge of their child’s follow-up. The first theme was further categorised into three subthemes: Health care professionals’ lack of knowledge and experience with rare conditions, Lack of coordinated health care, and The many unknowns in terms of prognosis, treatment, and function.

Health care professionals’ lack of knowledge and experience with rare conditions

Twenty-nine of the papers raised issues related to an experienced lack of knowledge about and experience with rare conditions among health care professionals. As a consequence, parents experienced uncertainties regarding the child’s diagnosis, prognosis, treatment and/or consequences of the rare condition [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. More specifically, parents reported diagnostic delays [ 27 , 29 , 50 ], and health care professionals that could not provide the information they needed about the rare condition once diagnosis was set [ 27 , 30 , 34 , 35 , 36 , 39 , 48 ]. Parents did not receive the guidance normally provided within the health care system [ 27 , 33 , 41 , 42 , 43 ], which could lead to a loss of trust and confidence in those who are meant to be the experts [ 32 , 46 , 51 , 52 ]. Other consequences of a lack of knowledge within the health care system could be the unintended consequence of delaying treatment [ 27 , 37 ]. Parents felt frustrated or troublesome when health care professionals did not understand what they believed to be their child’s health care needs [ 35 , 41 , 42 ].

The lack of knowledge within the general population strengthened the parents’ needs for health care professionals to have relevant, deep, and extensive knowledge and expertise [ 53 ]. One study specified that it was not the lack of competence or knowledge per se that parents found difficult, but what they perceived as the physicians’ attitude; their (un)willingness to admit their shortcomings and to seek information and advice [ 51 ] or to properly prepare before the consultation [ 30 , 54 ].

Several categories of health care services were mentioned in the included studies, ranging from specialized health care services (such as specialized hospital settings and treatment teams), local health care services (such as general practitioners, local hospitals), and professional caregivers in the families’ homes (such as health care assistants). Eight studies specifically raised the issue of a lack of knowledge and diagnostic expertise within local levels, even after the child’s diagnosis had been set [ 31 , 33 , 37 , 40 , 49 , 51 , 52 , 55 ].

Lack of coordinated health care

Several studies mentioned a general lack of coordination across systems or sectors in the plan of care for the child with a rare condition, even in cases of complex care needs or long-term intensive support [ 27 , 29 , 31 , 36 , 49 , 52 ]. Several studies included overwhelming parental narratives of fragmented care, with medical teams working in silos instead of integrating the family’s needs, leading to repeated consultations and numerous medical appointments with a range of clinicians in different hospitals [ 27 , 29 , 30 , 31 , 37 , 40 , 44 , 50 ]. A lack of coordinated care could contribute to a delayed diagnosis [ 55 ] and feelings of depersonalization, since parents had to tell and re-tell their story to new health care providers [ 31 ].

Parents believed that treatment of rare conditions should be organized within standardized and specialized follow-up care systems or centers of expertise with a main health care provider to coordinate care [ 39 , 44 ]. In cases where parents had received advice and follow-up from specialized units, this was experienced as positive and strengthened their trust in the quality of the child’s care [ 33 , 45 , 48 ]. Having the same caregivers over time was perceived as extremely important for families, because it led to enhanced availability and continuity [ 53 ]. In one study however, parents explicitly said they did not feel the condition’s rarity was an issue, and they therefore did not feel a need for specialized support services [ 37 ].

The many unknowns

The lack of knowledge within the health care system led to many unknowns due to a delayed or complicated diagnostic and treatment process with several consultations [ 27 , 30 , 31 , 38 , 39 , 40 , 41 , 47 , 48 , 49 , 53 , 54 ]. The diagnostic process and first phase of the child’s life had therefore been demanding for many parents [ 32 , 40 , 48 , 53 , 56 ]. The longer and more complex the diagnostic process, the more stress the parents felt [ 50 ]. Although knowing their child had a rare condition was distressing, receiving a diagnosis was experienced as a relief and a first step towards treatment and support [ 40 , 50 ]. Parents felt that they were responsible for the next steps after a diagnosis was set [ 27 ], but the complexity of the child’s diagnosis could complicate their understanding of what was to come [ 36 ].

The many unknowns triggered parents’ feeling of being abandoned to their fate, having to cope with the child’s illness on their own, and with an overall feeling of not being understood [ 34 , 36 ], which complicated the parents’ process of adjustment and coping [ 28 , 37 , 50 ].

Caregivers had several questions regarding the child’s future, and were worried about whether their child would be capable of doing things independently, how cognitive development would unfold, and whether the child would be able to live on their own in the future [ 29 , 33 , 39 , 44 , 46 , 52 ]. The many unknowns called for more support and guidance [ 39 , 42 , 43 ]. However, advices from health professionals could be inadequate and vary across levels of health care services [ 34 , 42 ], and limited evidence-based guidance complicated parents’ efforts to understand and compare risks and benefits when considering treatment alternatives [ 33 ].

Theme 2: Responsibilities and challenges

All studies described how parents experienced responsibility for their child’s medical care and handled challenges associated with the child’s diagnosis and everyday life. Theme 2 was categorised into four subthemes: Society’s lack of information and knowledge, Changes and adjustments in everyday life (work, parenthood, social life), Parents as coordinators, advocates, and experts, and Emotional reactions.

Society’s lack of information and knowledge

Parents often spent considerable time explaining their child's condition when meeting new people in settings such as playgrounds, shopping centres, or schools, an information task some parents experienced as demanding [ 28 , 45 , 48 , 49 , 53 , 57 ]. Nevertheless, they felt responsible for raising awareness about the rare condition [ 45 , 57 ], even when it felt difficult to explain to other people what their daily life looked like [ 31 , 34 , 35 ]. The challenge of explaining could be even greater if the child’s diagnosis was not visible to others, since caregivers could struggle to explain the child’s needs for special support [ 39 , 43 ]. The condition’s complexity could complicate the process of sharing information to others, especially if parents did not feel knowledgeable themselves to adequately explain [ 50 ], and parents missed reliable sources of knowledge where they could find information [ 30 , 31 , 36 ]. Lack of knowledge also had consequences in school settings [ 28 , 39 , 42 ] or public institutions when applying for social rights or benefits [ 55 ]. In some studies, the lack of understanding was a challenge also within the extended family, which reduced the possibilities of social support [ 45 , 47 , 52 ].

Social experiences among strangers and a general lack of knowledge in society could be demanding due to staring or comments if the child looked different or behaved differently [ 28 , 37 , 38 , 41 , 43 , 44 , 46 , 49 , 50 , 57 ]. Questions from others and/or a need to explain the difference was experienced as demanding by some parents [ 45 ], and some used preemptive and active strategies, hoping to fend off questions and stares [ 57 ]. Parents also described anticipated or experienced social stigma and taboo as challenging [ 44 , 46 , 49 , 50 , 57 ].

Changes and adjustments in everyday life (work, parenthood, social life)

Parents described how having a child with a rare condition had an impact on the whole family, siblings included [ 29 , 32 , 33 , 38 , 41 , 44 , 45 , 48 , 50 , 52 , 53 , 55 , 58 , 59 ].

Responsibility for the children and their care was described as intensive and demanding, and affected parents’ day-to-day living [ 37 , 39 , 46 , 49 , 50 , 51 ]. Coping with challenging day-to-day experiences and in some cases living in high alert over time was described as exhausting [ 31 , 36 , 49 ]. Because of the many daily challenges, levels of conflict could arise between spouses/partners and affect their relationship [ 29 , 32 , 38 , 44 , 47 , 52 ]. In contrast, three studies mentioned that the challenges could strengthen feelings of togetherness between the parents or within the family [ 29 , 52 , 58 ]. In one study, parents had specific recommendations for couples in order to preserve marriage and other relationships [ 45 ]. Lack of support in the larger family system could also lead to a higher level of conflict within the affected family [ 52 ]. Nevertheless, the priority was given to the child’s needs [ 29 , 45 , 58 ].

Some rare conditions present with specific behavioural or medical challenges with an impact on the family’s daily life. Hence, parents had to handle nutritional problems [ 53 ], food-seeking behaviours [ 39 , 45 , 54 ], communication problems [ 39 , 43 , 53 ], and behavioural problems [ 49 ]. The child’s condition could affect, complicate, or challenge the parent–child relationship, due to problems with communication and cognitive functioning, and/or behavioural characteristics that could be associated with the condition [ 28 , 43 , 45 , 48 , 53 ]. Treatment demands could break the child’s trust in the parents as their guardians against painful experiences [ 32 , 38 ], also affecting the parent–child relationship. Difficulties were especially challenging when the child could not express his or her own needs, making it very difficult for the parents to know whether their child was in pain or was in need of something [ 48 ]. During adolescence and early adulthood, parents mentioned how adherence issues to treatment could reduce the child’s long-term independence, and rise concerns about their child's ability to manage their own medical needs [ 33 ], possibly also affecting the child-parent relationship. In social settings, parents felt the need to shield their child from other people’s attitudes, fearing that the child’s self-perceptions could be negatively affected if people reacted to the child’s behaviour or the rare disease [ 50 , 57 ].

Demands associated with the rare condition led parents to feel torn between caring for their child and work obligations [ 27 , 47 , 49 , 55 ]. They felt that they had to inform the work place about their situation [ 57 ] or seek a different work situation [ 29 , 45 , 54 , 59 ], when the child’s care was described as a part-time job in itself [ 27 , 59 ]. Additional care needs also led parents to struggle with finding time for personal and/or social activities [ 30 , 46 , 48 , 55 ], and complicated the preservation of social relations outside the family [ 32 , 39 , 54 , 56 ]. Plans were difficult to make or had to be adjusted to the situation because of the many insecurities associated with daily care and/or treatment demands [ 41 , 51 , 55 ].

Due to medical or psychological problems related to the child’s diagnosis, caregivers experienced difficulties in looking after their child and provide the best upbringing [ 39 ]. Hence, in-home caregivers were necessary in some families. Still, finding suitable in-home caregivers that parents felt they could trust, and welcoming them into their private home could feel challenging and invading [ 31 , 59 ].

Parents as coordinators, advocates, and experts

Due to the lack of knowledge within the health care system, parents were the ones finding out whether support was existing and available, requesting care, social aid or benefits, or other resources they in some cases did not manage to receive, and took on the arduous and demanding responsibility of coordinating the follow-up of their child [ 27 , 29 , 30 , 31 , 32 , 37 , 39 , 41 , 42 , 46 , 48 , 49 , 55 ].

Several studies shed light on parents’ struggle to get what they believed should be proper care, being the ones noticing or bringing up that something was wrong with their child, being perceived as difficult and demanding, or having the feeling that health care providers did not believe them or even blamed them for the child’s symptoms [ 27 , 29 , 30 , 31 , 32 , 35 , 37 , 38 , 40 , 41 , 42 , 46 , 47 , 49 , 51 , 53 ]. Being dependent upon referrals and access to other necessary aids created a feeling of disempowerment in some parents, if such help was not provided [ 27 ]. Caregivers also felt they took on the responsibility for medical care they did not have any competence for in the first place, such as handling nutritional adjustments, educational needs, and/or managing other problems related to the diagnosis [ 47 , 50 ].

Due to a lack of dialogue between health care professionals, parents experienced medical appointments as repetitive in nature, and the need to tell their child's and family's story repeatedly across consultations [ 30 , 53 ]. Parents described spending energy and time looking for medical treatment that could alleviate their child’s symptoms [ 47 ], hoping to regain some control by taking on the responsibility of researching their child’s health care needs [ 32 ]. Some parents, or the larger family, also took the responsibility of finding and trying out treatment alternatives, in the hope of alleviating their child’s suffering [ 46 , 52 ].

Parents also felt responsible for special arrangements in school, social activities, interpersonal relationships, general life adjustments and assistance from psychological support teams, in addition to the family’s financial security [ 28 , 42 , 44 , 45 , 46 , 47 , 52 ]. One study described how school and health care settings also relied on parents’ knowledge and information to coordinate the child’s needs [ 42 ].

Parents labelled themselves as fighters, saviours, and navigators for their child, in their efforts to be heard [ 31 , 37 , 53 ] and described the paramount need to stand up for the child, intervene, negotiate, or act on the child's behalf, which could sometimes mean less time for caring for the sick child [ 44 , 45 ].

The lack of knowledge about the child’s rare condition led parents to search for information on the internet, but missed guidance from health care providers on this search [ 27 , 34 , 35 , 44 ]. They tried to be critical of the information they found and looked for what they considered to be reputable sources, such as scientific journals, and also connected with health care providers with specialized knowledge [ 27 ]. As a consequence of this extensive and ongoing search for information, in addition to their lived experiences, parents became experts on their child’s rare condition and felt they had acquired more knowledge about the rare condition than the health care providers [ 29 , 30 , 35 , 36 , 37 , 51 , 52 , 55 ]. Parents could feel that care providers’ knowledge was based on outdated information, whereas they had read more recent studies and were more updated on relevant research [ 30 ]. Nevertheless, several studies revealed that some parents did not feel that their experience was valued, acknowledged, or sought by health care providers [ 31 , 35 , 36 , 53 ]. This reversal of traditional parent–professional roles was experienced as difficult and an additional responsibility for some parents [ 28 ], who frequently felt they needed to be the expert “home doctors” [ 28 , 35 , 45 , 50 , 51 ]. Other studies showed that some parents treasured feeling as experts in their child’s care, and that understanding complex medical information could increase parents’ self-confidence [ 29 , 32 , 35 ].

Caregivers described how they had to monitor whether or not symptoms were developing in their child, for example whether their child was gaining weight or whether problems were related to the diagnosis or the child’s personality development [ 39 ], and in some cases also felt they were responsible for treatment decisions [ 28 ].

Emotional reactions

Parents described a wide range of emotional reactions, such as feelings of shock, anxiety and fear, lack of control, defencelessness, depression or loss, denial, self-blame and guilt, helplessness, and distress [ 28 , 29 , 32 , 33 , 34 , 35 , 36 , 38 , 41 , 42 , 44 , 45 , 46 , 47 , 49 , 51 , 52 , 53 , 55 ]. Uncertainty, unpredictability, and ambiguity characterized everyday life for many parents, or they felt trapped in a box or square that they could not get out of [ 43 , 44 , 46 , 53 ]. Feelings such as disbelief, displacement, anger, frustration, or pain were also described [ 29 , 31 , 35 , 37 , 40 , 44 , 45 , 54 ], eventually followed by feelings of acceptance [ 47 , 53 ]. In cases of genetically inheritable disorders, parents also felt guilt or fear of passing on the disorder to their children [ 36 , 41 ]. Life was described as a rollercoaster or a constant battle [ 37 , 38 , 44 ]. In one study, parents described how they felt they were in a movie, watching something they struggled with understanding was their own life, being centre stage and managing complications and disease manifestations, they had never imagined [ 49 ]. Having to cope with their child’s pain, fear of death, or the child’s own grief over the rare condition acted as an additional worry for parents [ 38 , 43 , 44 , 52 , 53 ].

Parents suffer because, firstly, their child’s illness requires so much attention, time, and energy that the physical and emotional wear and tear sooner or later takes its toll [ 36 ]. The many emotional reactions, such as powerlessness, threatened the parents’ belief in their own parenting skills [ 32 , 38 ]. Several studies also shed light on physical symptoms of exhaustion, physical burnout, insomnia, or illness in parents of children with a rare condition [ 30 , 32 , 36 , 42 , 47 , 59 ].

The concern regarding potential social reactions was a reality for many parents [ 28 , 43 , 46 , 47 ]. Informing others was associated with feelings of depression and anxiety [ 48 ]. Fear or experiences of bullying was also a prominent aspect for several parents [ 41 , 46 ]. Parents also described the immense emotional cost of shielding or defending their child against social misconceptions and reactions, due to the social or physical visibility of the condition, sometimes leading to social avoidance [ 28 , 32 , 37 , 38 , 41 , 43 , 44 , 49 ].

Having to cope with many unanswered questions regarding the child’s future care and treatment options caused feelings of loneliness, helplessness and insecurity [ 27 , 28 , 29 , 32 , 34 , 36 , 37 , 38 , 39 , 40 , 44 , 47 , 49 , 52 , 54 , 55 , 56 ]. Fragmented care delivery increased families’ emotional load [ 30 , 37 , 44 , 50 ]. The overall lack of understanding and knowledge about the rare genetic disorder and its treatment led to anger, frustration, sorrow, and feelings of isolation [ 28 , 42 , 44 ], or a sense of loneliness [ 36 , 50 ], due to the lack of strategies or tools needed to deal with the situation. Parents could find it difficult to share their experiences and what they went through, which led to feelings of isolation [ 31 , 34 , 48 , 49 ]. Feeling isolated could also be triggered by a lack of understanding from close friends or family [ 49 , 58 ], or from health care providers [ 27 , 29 , 30 , 41 , 52 ]. In contrast, social support and normalising everyday life, such as going to work, reduced feelings of isolation [ 48 , 56 ]. Parents were also concerned over how the impact of illness affected their child's quality of life and/or daily life [ 28 , 33 , 43 ].

Theme 3: Factors promoting positive experiences in parents

All studies except two presented findings related to positive adjustment in parents of children with a rare condition. The third theme was categorised into three sub-themes: Engaged and understanding health care professionals, Benefits of social support, and Protective factors and coping mechanisms.

Engaged and understanding health care professionals

Parents shared how relieving it was to be treated with respect and knowledge from the health care professionals in charge of treatment and feel that their problems were taken seriously [ 41 ]. Care professionals honouring the families' knowledge and recognising that parents had first-hand experience with the condition was important [ 30 , 31 ]. The development of self-reliance and trust in their ability to cope with problems could be enhanced when parents’ perception of subjective vulnerability was counterbalanced by support from professionals [ 35 , 53 ].

The importance of professional caregivers’ personal characteristics was underlined, so that a trusting relationship could be built between parents and helpers [ 53 ]. Respect, compassion and empathy, emotional support and involvement, being treated with sensitivity, tact, and kindness, continuity, knowledge and availability, and boosting parents’ knowledge were described to be ideal characteristics in health care professionals [ 34 , 36 , 48 , 53 , 54 ]. Personal and direct communication was also central when information was provided [ 44 ]. Connection with care professionals was achieved when they were experienced to be kind, caring, present, understanding and listening, while also being real and truthful about the situation [ 30 , 37 , 42 , 48 , 53 , 54 ]. Trust depended on the degree to which professionals managed to be honest about their lack of knowledge and managed to show that they understood the emotional impact of the rare condition on the families’ lives [ 36 , 48 , 51 ].

Benefits of social support

Social support was experienced as hugely important, protected against emotional distress [ 35 , 48 , 56 , 58 ], and provided parents with much necessary support when the child’s help needs exceeded the parents’ available resources [ 36 ]. Daily life, such as being at work, normalised parents’ situation and enabled them to have social interactions, which could have a protective social function [ 48 , 54 , 59 ]. Social and emotional support could also be found in faith communities and helped parents coping with their situation [ 56 ]. Specific and practical support, on the other hand, was complicated by parents’ fear that others could not correctly understand their child’s care needs and they therefore could not trust support to be given [ 45 ]. In one study, fathers did not want social support, since handling things alone or within the nuclear family acted as a protective strategy and a buffer against exposure to the courtesy stigma that could be triggered if help was sought or received [ 57 ].

The larger family may normally provide additional support, which was confirmed in one study [ 58 ]. However, cultural or societal frameworks could lead the larger family, such as older family members and grandparents, to blame the child’s parents for the rare condition [ 47 , 52 ], or feel shame about their grandchildren, which led to a lack of support within the larger family [ 52 ]. In yet other families, the genetic aspects of the condition meant that several family members were affected; reducing the opportunities for support, and/or caregivers could find it difficult to ask for help [ 28 ].

Other people’s level of understanding and positive attitude was described as central for parents to feel supported by friends and others [ 45 ]. Therefore, the emotional, practical, and social benefits of talking to others with similar experiences was highlighted as important by parents in several studies [ 27 , 28 , 29 , 35 , 36 , 39 , 40 , 41 , 45 , 47 , 48 , 50 ]. Being active members of patient associations where parents could discuss challenges, share experiences, and provide each other with information and advice, was described as a main source of social support [ 27 , 29 , 44 , 45 , 50 ], and a necessary asset for reducing feelings of isolation [ 27 , 29 , 33 , 35 , 39 , 48 , 50 ]. Nevertheless, some parents felt that attending support conferences and meeting other parents had increased their worries for the child’s future [ 45 ].

The lack of knowledge within the health care system and society as a whole, leading to an absence of clear, understandable and accessible public information, strengthened the importance of searching for information on the Internet and seek support and feel connected to other parents who had undergone the same situation [ 27 , 34 , 35 , 40 , 42 , 45 , 55 ]. The asset of online peer support was described to be its flexibility and availability, with easy access to other parents’ experiences and recommendations on a daily basis or whenever needed [ 27 , 35 , 44 ]. Parents were, however, well aware that the Internet also could be an anxiety provoking and frightening tool [ 35 , 44 ].

Protective factors and coping mechanisms

Several studies mentioned individual characteristics that had strengthened parents’ coping mechanisms. Willpower, perseverance, and courage seemed particularly important, as well as the ability to adjust and plan everyday life so that it matched the child’s needs [ 35 , 37 , 42 , 45 , 47 , 48 , 52 ]. A sense of agency and self-reliance also strengthened parents’ ability to cope and trust in their ability to help and care for their child when problems arised [ 32 , 33 , 35 , 37 , 38 , 53 , 57 ]. High levels of health literacy was also explicitly described as helpful in one study [ 35 ]. Parents also aimed at increasing their child’s sense of agency, encouraging the child in participating in treatment decisions or defending him-/herself from negative social reactions [ 52 , 57 ]. Parents had also experienced that demanding experiences had strengthened their self-confidence, changed their outlook on life, and increased their empathy skills and understanding of other’s challenges [ 32 ].

Families described a process of normality reconstruction, incorporating the child’s condition with its consequences, and a re-organizing of family life based on the needs of the child, which appeared to give parents a sense of control over their situation [ 50 ]. Having the same condition as their child was also described as enhancing parents’ coping skills, as they had previous experience with the disease [ 41 ]. Normalization and acceptance was facilitated if the parents felt the child’s situation was stable. Nevertheless, the lack of knowledge regarding the condition’s progress and outcome created a fragile sense of control, and could be easily shattered in case of unexpected events [ 44 , 50 ].

Parents developed strategies and knowledge themselves, learning by doing [ 42 ]. Focusing on daily tasks and everyday life was a way of coping with grief and loss [ 28 , 52 ]. Religious beliefs, or mindfulness practice and yoga, were described as helping caregivers revisit life's challenges, accept trials and tribulations, and find strength to cope [ 45 , 47 , 52 , 56 ]. Parents described the importance of identifying activities or daily routines that could strengthen their own and the family’s emotional coping [ 45 , 59 ]. The importance of focusing on positive aspects of being a parent of a child with a rare condition [ 44 ], as well as feelings of gratitude and hope also strengthened parents’ adjustment to the rare condition [ 38 ].

Parents’ experiences of having a child with a rare genetic disorder have previously not been systematically reviewed. The present review examined the qualitative literature methodically, in order to identify parents’ experiences of having a child with a rare genetic disorder. Findings were categorized according to three main themes: Parents’ experiences with health care, Responsibilities and challenges, and Factors promoting positive experiences in parents. This systematic review demonstrates that parents of children with rare genetic disorders share many common challenges, such as a lack of knowledge in the health care system as well as in society in general, a lack of coordinated care, and lack of available information about rare disorders. Consequently, parents experience that they have to be experts on their child’s rare disorder, coordinators in the health care system, and act as advocates for their child. Many parents felt isolated and alone, and experienced a change in their social situation when they became parents to a child with a rare disorder; especially mothers described challenges with working fulltime and having a child with a rare disorder. Few articles focused primarily on protective factors or parents’ coping mechanisms. However, the synthesis of the results demonstrated that all but two studies presented findings that shed light on factors promoting positive experiences in parents, such as engaged and understanding health care professionals, benefits of contact with others in a similar situation and social contacts in general, and the use of personal coping mechanisms such as educating themselves, focusing on daily activities, religious beliefs and feelings of gratitude and hope.

Parents’ experiences with the health care system

Parents mentioned health care professionals’ lack of knowledge and lack of experience about rare disorders in the majority of the studies. Lack of knowledge, and its negative consequences such as delays in obtaining an accurate diagnosis and maltreatment [ 60 , 61 ], is not novel news. Lack of knowledge is indeed a major barrier for people with rare disorders [ 62 ], and our systematic review demonstrates that this also is true for parents to children with rare disorders.

In 2009, the European commission requested that all European countries should elaborate and adopt plans and national strategies for rare diseases. Sadly, this seems to be easier said than done [ 63 ]. Collecting and sharing knowledge across different countries, and for different rare disorders, are important methods to increase knowledge. Unfortunately, the small number of available individuals to include in the research on rare disorders adds an extra challenge to this task. The readers of published literature may also be few, giving this research low prestige and more difficult to fund [ 64 ]. International collaboration is therefore of major importance, and research programs for rare disorders across countries, such as projects promoted by the European Joint Programme on Rare Diseases (EJP RD) [ 65 ], should be encouraged. European Reference Networks (ERN) were founded on the principle that experts and specialists need to communicate and collaborate across countries if we are to solve challenges related to rare conditions [ 66 ]. However, the effect these ERN’s have on individuals’, families’ and health care professionals’ experiences on access to knowledge and treatment of rare disorders remains unanswered and should be prioritized in future research.

Some individuals live with an undiagnosed condition and the International Rare Diseases Research Consortium (IRDiRC) suggest that this group of individuals should enter a globally coordinated diagnostic and research pipeline [ 67 ]. Until such a pipeline is up and running, existing international collaboration is of immeasurable value. The importance of national and international networks, and databases such as DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) [ 68 ] and GeneMatcher [ 69 ], to identify other ultra-rare patients and researchers interested in the gene or disease cannot be overestimated.

Health care professionals and patient support organizations must continue to work together as they already do in the North American National Organization for rare disorders (NORD) and European Organization for rare diseases (EURORDIS). Although the awareness about rare disorders is increasing in Asia [ 70 ], there is room for improvement, especially in Africa [ 71 ]. Results from the current study demonstrate clear unmet medical needs, lack of knowledge on a societal level, with corresponding psychological consequences for parents of children with a rare disorder, problems that may be exacerbated in countries with less available resources. Hence, European and North-American actions, such as the organization of ERNs or NORD, could possibly have the potential to address some of the unmet needs revealed in the present study, and inspire similar actions in regions with fewer resources world-wide.

Several of the studies mentioned that the children had to see several different specialists before the diagnosis was set. Challenges continued also after the diagnosis, since far from all questions parents had had been resolved. For rare disorders, and especially for ultra-rare disorders, the current study confirms that parents face many unknowns, just to mention a few: What is the prognosis? Will there be treatment available? Will my child get access to treatment? For more well-known chronic disorders, parents will not need to ask most of these questions, because answers are obvious and health care professionals may provide them immediately. In contrast, parents of children with rare disorders often continue to search for knowledge about the disorder and possible treatment. Lack of coordinated care was identified as a major challenge for the parents in the present review. When parents of children with spinal muscular atrophy were asked to provide advice that could improve the follow-up of their child, they suggested health care professionals to designate a coordinator for every family [ 72 ]. Future research should investigate whether this is a solution that could improve parents’ health care experiences when the child has a rare condition.

Responsibilities and challenges

In addition to health care professionals’ lack of knowledge, many parents described a lack of available information about their child’s rare disorder, and a general lack of knowledge in society. The parents described how they became the experts on the rare disorder, acted as coordinators for their children’s follow-up, and became advocates for their child. A review on adults with a rare disorder also revealed that people affected by a rare condition considered themselves as “expert patients”; They educated themselves and became experts on their condition, because of health care professionals’ lack of knowledge and experience with the condition [ 62 ]. Health care professionals should see this gained expertise as a value [ 73 ]. However, research may indicate that some health care providers feel challenged by lay knowledge [ 74 ]. Instead, health care professionals should use the expert knowledge parents of children with rare disorders have as a valued resource that may optimize care. Previous research has shown that the parents’ voices are vital to influence and guide service development [ 75 ], and a critical element in creating responsive, meaningful, and widely accepted policies [ 76 ].

Several studies demonstrated how care needs and consequences of the rare disorder had forced parents to make changes in their social life, such as cutting down work-hours or quitting their job, and seeing friends and family less. For some, this had promoted a sense of isolation and almost all studies described how parents had to cope with a range of emotional reactions in their daily lives that could potentially affect their psychological adjustment. Parents of children with a rare condition have additional stressors, including balancing work and family, time constraints, stress, and feelings of “doing it all” [ 77 ]. Research on rare craniofacial conditions has demonstrated that parental distress has the potential to impact the child’s own emotional development [ 78 ]. In contrast, parents who feel they have managed to adjust positively to their child’s condition will probably be better equipped to help their child to develop a positive and strong self-image [ 79 ], in line with research showing that parents’ sense of self-efficacy in their ability to care for their child is central for the development of the child’s well-being [ 80 ].

Although parents of children with congenital genetic disorders may have heritable concerns regarding their child’s genetic status, this was not a prominent theme in the studies included in this review. One reason may be that the issue of heritability was not specifically addressed in these studies. Concerns regarding heritability may be sensitive for parents to share, and thus may be missed unless specifically addressed.

Factors promoting positive experiences in parents

Studies focusing primarily on factors and coping mechanisms that have a positive effect on parents of children with rare disorders are lacking. None of the included studies systematically investigated protective factors that could promote coping. Nevertheless, most studies revealed positive factors and parental coping mechanisms. As many of the negative factors, such as lack of knowledge and lack of treatment, may not be solved immediately, a focus on factors promoting positive experiences may be clinically helpful. Interestingly, in all but two of the studies, parents mentioned factors important to them as positive. Parents described the importance of having a social network and to be able to work outside of home in order to get some normalcy in life. It may therefore be important to encourage parents to continue in their jobs, and for society and employers to facilitate the work situation in an optimal way for parents [ 81 ], as well as encourage the parents to find ways to keep up their social life and contact with family and friends.

The parents considered it very beneficial to be in contact with others in a similar situation, i.e. parents of other children with the same diagnosis as their own child. For some rare disorders, there may be national or international patient support groups. For most rare disorders, this is missing, and parents may find support groups in social media such as Facebook. Information shared on support groups on Internet may be valuable to families with a member with a rare disorder [ 82 ]. A recent study demonstrated that most of the support groups on Facebook are private groups [ 83 ]. For many parents, these groups are the only place where they find others in a similar situation, as well as information about the disease and possible treatment options. A lack of professional involvement in these private groups may challenge the scientific quality of its content. Researchers and health care professionals could be more involved in such groups, as it could be of benefit to both parties. However, Facebook, or other similar web-sites on the Internet, are not secure platforms to share sensitive data, and parents and health care professionals should therefore be careful with their use.

An engaged and understanding doctor was also of high value to the parents, and these qualities in a health care professional seemed to be more important than the health care professional’s actual level of knowledge. Although health care workers’ lack of knowledge may be frustrating to parents, a lack of interest or a lack of respect for the parents’ knowledge may be even more damaging, and lead to a deterioration of the relationship between parents and health care professionals, which could be followed by less optimal health care for the child as a consequence. Though the lack of knowledge is disturbing, it is important to know that for some disorders, such as for example many ultra-rare disorders or disorders of N -of-1, little knowledge is available, and will perhaps be lacking for many years. It is therefore very important for health care professionals to show engagement, sensitivity, and understanding irrespective of the level of knowledge about the rare condition [ 72 , 84 ]. Research on how health care professionals can provide optimal care for parents of children with rare disorders, despite a lack of competence and knowledge, should be prioritized, as well as research to minimize the gap of lack of knowledge. Health care professionals should be trained to handle situations where they do not have the necessary knowledge, and where information may be replaced by uncertainties. Meeting the parents with confidence, interest and respect will not act as a substitute to a lack of knowledge; however, it may still be of help to the parents. Less use of the health care system and poorer health may be the result of parents’ mistrust to health care professionals [ 85 ].

The majority of participants in the included studies were mothers. This could reflect that mothers take more responsibility for being the child’s primary caregiver. Indeed, several studies demonstrated that the father was the primary caretaker and provider of the family’s economy, by keeping a full time job. However, more research on fathers’ experiences is warranted.

Strengths and limitations

The strengths of this literature review lie in the methodological and systematic approach, investigating the lived experiences of being a parent or primary caregiver of a child with a rare genetic disorder from a qualitative perspective. It is, however, also important to acknowledge some limitations with the present review. First, some methodological challenges were encountered. Given the many thousands different rare conditions, identifying a good search strategy was important, and the search strategy was therefore discussed in detail with a specialist librarian before conducting the search. A different methodological approach could have been to specifically include some more “common” rare congenital genetic disorders within the search process. However, choosing which diagnoses to include would have been a methodological challenge, and this method was therefore not chosen in the present review.

Articles on specific rare diagnoses in which “rare disease”, or its synonyms, were not included in the title, abstract or keywords, could therefore have been missed. Hence, chances were possibly higher not identifying rare conditions with higher prevalence rates, compared to very rare or ultra-rare conditions, and may have influenced results. However, in order to counterbalance this limitation, we used the search words rare, orphan, diseases, disorder*, diagnosis*.

Another methodological challenge was that some studies presented quotes without the context they were a part of, or presented some results very shortly, complicating the synthesis of the results in the present review. One paper presented their results as part of the discussion, also complicating the extraction of data for this review. Further, few studies explicitly explored the potential uniqueness of the rarity of a condition, investigating whether challenges that are identified have a similar or differential impact on individuals, depending of the specificity of the condition.

A strength of this study is that we are three authors with different backgrounds. CVDL and KBF both have experience in qualitative research. CVDL is a clinical geneticist with several years of experience of working with families with rare disorders. KBF is a psychologist and has vast knowledge about rare disorders and the psychosocial consequences of living with a rare disorder. IN is a doctor in training in pediatrics with less knowledge about rare disorders, which was seen as a strength, since IN could challenge CVDL and KBF’s potential pre-conceptions about rare disorders when discussing the synthesis of the results, reducing the risk of bias.

The current review demonstrates that parents of children with a rare genetic disorder face many common challenges across different conditions. Health care professionals’ lack of knowledge seems to be a major obstacle for parent’s ability to care for their child, and they should be trained to handle and optimize meetings with the families in spite of uncertainties and lack knowledge. Parents also described the importance of having social networks and the benefit of being in contact with parents of children with similar challenges as themselves, which could possibly counteract the negative impact of a lack of knowledge in health care services and society in general. There is a need for more coordinated care for children with rare disorders, and a more holistic approach in the follow up of the children and the parents. The expertise of the parents should be valued. The development of more international collaboration on research, diagnostics, creating and making available scientific correct information understandable for health care professionals and lay people should be prioritized. Unmet medical needs and the lack of knowledge have clear psychological consequences for the parents, and therefore need to be addressed by health care policies.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

What is a rare disease? https://www.eurordis.org/content/what-rare-disease : EURORDIS; 2020 [updated 21/07/2020; cited 2021 Nov 30]. Available from: https://www.eurordis.org/content/what-rare-disease.

Rare Diseases FAQ https://www.genome.gov/FAQ/Rare-Diseases [updated Jan 10 2020; cited 2021 Nov 30]. Available from: https://www.genome.gov/FAQ/Rare-Diseases .

Boycott KM, Vanstone MR, Bulman DE, MacKenzie AE. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet. 2013;14(10):681–91. https://doi.org/10.1038/nrg3555 .

Article   CAS   PubMed   Google Scholar  

Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019;179(6):885–92. https://doi.org/10.1002/ajmg.a.61124 .

Article   PubMed   Google Scholar  

Cohen JS, Biesecker BB. Quality of life in rare genetic conditions: a systematic review of the literature. Am J Med Genet A. 2010;152(5):1136–56. https://doi.org/10.1002/ajmg.a.33380 .

Article   Google Scholar  

Waldboth V, Patch C, Mahrer-Imhof R, Metcalfe A. Living a normal life in an extraordinary way: a systematic review investigating experiences of families of young people’s transition into adulthood when affected by a genetic and chronic childhood condition. Int J Nurs Stud. 2016;62:44–59. https://doi.org/10.1016/j.ijnurstu.2016.07.007 .

Keinath MC, Prior DE, Prior TW. Spinal muscular atrophy: mutations, testing, and clinical relevance. Appl Clin Genet. 2021;14:11. https://doi.org/10.2147/TACG.S239603 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Cousino MK, Hazen RA. Parenting stress among caregivers of children with chronic illness: a systematic review. J Pediatr Psychol. 2013;38(8):809–28. https://doi.org/10.1093/jpepsy/jst049 .

Pinquart M. Parenting stress in caregivers of children with chronic physical condition—a meta-analysis. Stress Health J Int Soc Investig Stress. 2017. https://doi.org/10.1002/smi.2780 .

Brehaut JC, Kohen DE, Garner RE, Miller AR, Lach LM, Klassen AF, et al. Health among caregivers of children with health problems: findings from a Canadian population-based study. Am J Public Health. 2009;99(7):1254–62. https://doi.org/10.2105/AJPH.2007.129817 .

Article   PubMed   PubMed Central   Google Scholar  

Dellve L, Samuelsson L, Tallborn A, Fasth A, Hallberg LR. Stress and well-being among parents of children with rare diseases: a prospective intervention study. J Adv Nurs. 2006;53(4):392–402. https://doi.org/10.1111/j.1365-2648.2006.03736.x .

Pelentsov LJ, Fielder AL, Laws TA, Esterman AJ. The supportive care needs of parents with a child with a rare disease: results of an online survey. BMC Fam Pract. 2016;17:88. https://doi.org/10.1186/s12875-016-0488-x .

Zurynski Y, Deverell M, Dalkeith T, Johnson S, Christodoulou J, Leonard H, et al. Australian children living with rare diseases: experiences of diagnosis and perceived consequences of diagnostic delays. Orphanet J Rare Dis. 2017;12(1):68. https://doi.org/10.1186/s13023-017-0622-4 .

Beighton C, Wills J. How parents describe the positive aspects of parenting their child who has intellectual disabilities: a systematic review and narrative synthesis. J Appl Res Intellect Disabil. 2019;32(5):1255–79. https://doi.org/10.1111/jar.12617 .

Dodge JA, Chigladze T, Donadieu J, Grossman Z, Ramos F, Serlicorni A, et al. The importance of rare diseases: from the gene to society. Arch Dis Child. 2011;96(9):791–2. https://doi.org/10.1136/adc.2010.193664 .

Haffner ME, Whitley J, Moses M. Two decades of orphan product development. Nat Rev Drug Discov. 2002;1(10):821–5. https://doi.org/10.1038/nrd919 .

EURORDIS Kole A, Faurisson F. The voice of 12,000 patients. Experiences and expectations of rare disease patients on diagnosis and care in Europe: EURORDIS-Rare Diseases Eu. 2009.

Molster C, Urwin D, Di Pietro L, Fookes M, Petrie D, van der Laan S, et al. Survey of healthcare experiences of Australian adults living with rare diseases. Orphanet J Rare Dis. 2016;11(1):1–12. https://doi.org/10.1186/s13023-016-0409-z .

Nutt S, Limb L. Survey of patients’ and families’ experiences of rare diseases reinforces calls for a rare disease strategy. Soc Care Neurodisability. 2011. https://doi.org/10.1108/20420911111188443 .

Dodge JA, Chigladze T, Donadieu J, Grossman Z, Ramos F, Serlicorni A, et al. The importance of rare diseases: from the gene to society. Arch Dis Child. 2010. https://doi.org/10.1136/adc.2010.193664 .

Wästfelt M, Fadeel B, Henter JI. A journey of hope: lessons learned from studies on rare diseases and orphan drugs. J Intern Med. 2006;260(1):1–10. https://doi.org/10.1111/j.1365-2796.2006.01666.x .

Strauss A, Corbin J. Basics of qualitative research. London: Sage Publications; 1990.

Google Scholar  

Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1–9. https://doi.org/10.1186/2046-4053-4-1 .

O’Brien BC, Harris IB, Beckman TJ, Reed DA, Cook DA. Standards for reporting qualitative research: a synthesis of recommendations. Acad Med. 2014;89(9):1245–51. https://doi.org/10.1097/ACM.0000000000000388 .

Barnett-Page E, Thomas J. Methods for the synthesis of qualitative research: a critical review. BMC Med Res Methodol. 2009;9(1):1–11. https://doi.org/10.1186/1471-2288-9-59 .

Thomas J, Harden A. Methods for the thematic synthesis of qualitative research in systematic reviews. BMC Med Res Methodol. 2008;8(1):1–10. https://doi.org/10.1186/1471-2288-8-45 .

Baumbusch J, Mayer S, Sloan-Yip I. Alone in a crowd? Parents of children with rare diseases’ experiences of navigating the healthcare system. J Genet Couns. 2018. https://doi.org/10.1007/s10897-018-0294-9 .

Brewer HM, Eatough V, Smith JA, Stanley CA, Glendinning NW, Quarrell OW. The impact of juvenile Huntington’s disease on the family: the case of a rare childhood condition. J Health Psychol. 2008;13(1):5–16. https://doi.org/10.1177/1359105307084307 .

Cardinali P, Migliorini L, Rania N. The caregiving experiences of fathers and mothers of children with rare diseases in Italy: challenges and social support perceptions. Front Psychol. 2019;10:1780. https://doi.org/10.3389/fpsyg.2019.01780 .

Currie G, Szabo J. “It is like a jungle gym, and everything is under construction”: the parent’s perspective of caring for a child with a rare disease. Child Care Health Dev. 2019;45(1):96–103. https://doi.org/10.1111/cch.12628 .

Currie G, Szabo J. ‘It would be much easier if we were just quiet and disappeared’: parents silenced in the experience of caring for children with rare diseases. Health Expect Int J Public Particip Health Care Health Policy. 2019;22(6):1251–9. https://doi.org/10.1111/hex.12958 .

Feragen KB, Stock NM, Myhre A, Due-Tonnessen BJ. Medical stress reactions and personal growth in parents of children with a rare craniofacial condition. Cleft Palate Craniofacial J Off Publ Am Cleft Palate Craniofacial Assoc. 2020;57(2):228–37. https://doi.org/10.1177/1055665619869146 .

Gerstein MT, Markus AR, Gianattasio KZ, Le Mons C, Bartos J, Stevens DM, et al. Choosing between medical management and liver transplant in urea cycle disorders: a conceptual framework for parental treatment decision-making in rare disease. J Inherit Metab Dis. 2020;43(3):438–58. https://doi.org/10.1002/jimd.12209 .

Gilmore L. Supporting families of children with rare and unique chromosome disorders. Res Pract Intellect Dev Disabil. 2018;5(1):8–16. https://doi.org/10.1080/23297018.2017.1360152 .

Glenn AD. Using online health communication to manage chronic sorrow: mothers of children with rare diseases speak. J Pediatr Nurs. 2015;30(1):17–24. https://doi.org/10.1016/j.pedn.2014.09.013 .

Gomez-Zuniga B, Pulido Moyano R, Pousada Fernandez M, Garcia Oliva A, Armayones RM. The experience of parents of children with rare diseases when communicating with healthcare professionals: towards an integrative theory of trust. Orphanet J Rare Dis. 2019;14(1):159. https://doi.org/10.1186/s13023-019-1134-1 .

Griffith GM, Hastings RP, Nash S, Petalas M, Oliver C, Howlin P, et al. “You have to sit and explain it all, and explain yourself”. Mothers’ experiences of support services for their offspring with a rare genetic intellectual disability syndrome. J Genet Couns. 2011;20(2):165–77. https://doi.org/10.1007/s10897-010-9339-4 .

Myrin Westesson L, Sparud-Lundin C, Wallengren C, Baghaei F. A tortuous route to a capable fatherhood: the experience of being a father to a child with severe haemophilia. Haemophilia. 2015;21(6):799–805. https://doi.org/10.1111/hae.12781 .

Kleinendorst L, van den Heuvel LM, Henneman L, van Haelst MM. Who ever heard of 16p11.2 deletion syndrome? Parents’ perspectives on a susceptibility copy number variation syndrome. Eur J Hum Genet. 2020;28(9):1196–204. https://doi.org/10.1038/s41431-020-0644-6 .

Lim F, Downs J, Li J, Bao X-H, Leonard H. Barriers to diagnosis of a rare neurological disorder in China—lived experiences of Rett syndrome families. Am J Med Genet A. 2012;158A(1):1–9. https://doi.org/10.1002/ajmg.a.34351 .

Pousette Lundgren G, Hasselblad T, Johansson AS, Johansson A, Dahllof G. Experiences of being a parent to a child with amelogenesis imperfecta. Dent J. 2019. https://doi.org/10.3390/dj7010017 .

Nag HE, Hoxmark LB, Naerland T. Parental experiences with behavioural problems in Smith–Magenis syndrome: the need for syndrome-specific competence. J Intellect Disabil JOID. 2019;23(3):359–72. https://doi.org/10.1177/1744629519847375 .

Smith JA, Brewer HM, Eatough V, Stanley CA, Glendinning NW, Quarrell OWJ. The personal experience of juvenile Huntington’s disease: an interpretative phenomenological analysis of parents’ accounts of the primary features of a rare genetic condition. Clin Genet. 2006;69(6):486–96. https://doi.org/10.1111/j.1399-0004.2006.00624.x .

Somanadhan S, Larkin PJ. Parents’ experiences of living with, and caring for children, adolescents and young adults with Mucopolysaccharidosis (MPS). Orphanet J Rare Dis. 2016;11(1):138. https://doi.org/10.1186/s13023-016-0521-0 .

Vitale SA. Parent recommendations for family functioning with Prader–Willi syndrome: a rare genetic cause of childhood obesity. J Pediatr Nurs. 2016;31(1):47–54. https://doi.org/10.1016/j.pedn.2015.11.001 .

Weng HJ, Niu DM, Turale S, Tsao LI, Shih FJ, Yamamoto-Mitani N, et al. Family caregiver distress with children having rare genetic disorders: a qualitative study involving Russell–Silver syndrome in Taiwan. J Clin Nurs. 2012;21(1–2):160–9. https://doi.org/10.1111/j.1365-2702.2010.03583.x .

Wu Y-H, Sun F-K, Lee P-Y. Family caregivers’ lived experiences of caring for epidermolysis bullosa patients: a phenomenological study. J Clin Nurs. 2020;29(9–10):1552–60. https://doi.org/10.1111/jocn.15209 .

Zelihić D, Hjardemaal FR, von der Lippe C. Caring for a child with Bardet-Biedl syndrome: a qualitative study of the parental experiences of daily coping and support. Eur J Med Genet. 2020;63(4):103856. https://doi.org/10.1016/j.ejmg.2020.103856 .

Currie G, Szabo J. Social isolation and exclusion: the parents’ experience of caring for children with rare neurodevelopmental disorders. Int J Qual Stud Health Well Being. 2020;15(1):1725362. https://doi.org/10.1080/17482631.2020.1725362 .

Germeni E, Vallini I, Bianchetti MG, Schulz PJ. Reconstructing normality following the diagnosis of a childhood chronic disease: Does “rare” make a difference? Eur J Pediatr. 2018;177(4):489–95. https://doi.org/10.1007/s00431-017-3085-7 .

von der Lippe C, Frich JC, Harris A, Solbrække KN. Treatment of hemophilia: a qualitative study of mothers’ perspectives. Pediatr Blood Cancer. 2017;64(1):121–7. https://doi.org/10.1002/pbc.26167 .

Yang B-H, Mu P-F, Wang W-S. The experiences of families living with the anticipatory loss of a school-age child with spinal muscular atrophy–the parents’ perspectives. J Clin Nurs. 2016;25(17–18):2648–57. https://doi.org/10.1111/jocn.13312 .

Trulsson U, Klingberg G. Living with a child with a severe orofacial handicap: experiences from the perspectives of parents. Eur J Oral Sci. 2003;111(1):19–25. https://doi.org/10.1034/j.1600-0722.2003.00001.x .

Ragusa L, Crino A, Grugni G, Reale L, Fiorencis A, Licenziati MR, et al. Caring and living with Prader-Willi syndrome in Italy: integrating children, adults and parents’ experiences through a multicentre narrative medicine research. BMJ Open. 2020;10(8): e036502. https://doi.org/10.1136/bmjopen-2019-036502 .

Gueita-Rodriguez J, Famoso-Perez P, Salom-Moreno J, Carrasco-Garrido P, Perez-Corrales J, Palacios-Cena D. Challenges affecting access to health and social care resources and time management among parents of children with Rett syndrome: a qualitative case study. Int J Environ Res Public Health. 2020. https://doi.org/10.3390/ijerph17124466 .

Purcell HN, Whisenhunt A, Cheng J, Dimitriou S, Young LR, Grossoehme DH. “A remarkable experience of god, shaping us as a family”: parents’ use of faith following child’s rare disease diagnosis. J Health Care Chaplain. 2015;21(1):25–38. https://doi.org/10.1080/08854726.2014.988525 .

Tikkanen SA, Peterson BL, Parsloe SM. Courtesy stigma and social support: an exploration of fathers’ buffering strategies and blocking rationalizations. Health Commun. 2019;34(13):1543–54. https://doi.org/10.1080/10410236.2018.1504658 .

Bruns D, Foerster K. ‘We’ve been through it all together’: supports for parents with children with rare trisomy conditions. J Intellect Disabil Res JIDR. 2011;55(4):361–9. https://doi.org/10.1111/j.1365-2788.2010.01381.x .

Bruns D, Schrey C. Examining in-home care needs and work responsibilities for parents with children with a rare trisomy condition. Int J Dev Disabil. 2012;58(3):159–75. https://doi.org/10.1179/2047387712Y.0000000002 .

Syed AM, Camp R, Mischorr-Boch C, Houÿez F, Aro AR. Policy recommendations for rare disease centres of expertise. Eval Program Plann. 2015;52:78–84. https://doi.org/10.1016/j.evalprogplan.2015.03.006 .

Wallenius E, Möller K, Berglund B. Everyday impact of having a rare diagnosis. A Quest Study Vård i Norden. 2009;29(3):13–7. https://doi.org/10.1177/010740830902900304 .

von der Lippe C, Diesen PS, Feragen KB. Living with a rare disorder: a systematic review of the qualitative literature. Mol Genet Genomic Med. 2017;5(6):758–73. https://doi.org/10.1002/mgg3.315 .

Hedley V, Bottarelli V, Weinman A, Taruscio D. Shaping national plans and strategies for rare diseases in Europe: past, present, and future. J Community Genet. 2021;12(2):207–16. https://doi.org/10.1007/s12687-021-00525-4 .

Forman J, Taruscio D, Llera VA, Barrera LA, Coté TR, Edfjäll C, et al. The need for worldwide policy and action plans for rare diseases. Acta Paediatr. 2012;101(8):805–7. https://doi.org/10.1111/j.1651-2227.2012.02705.x .

European Joint Programme on Rare Diseases https://www.ejprarediseases.org/2021 [cited 2021 Nov 30].

Tumiene B, Graessner H, Mathijssen IM, Pereira AM, Schaefer F, Scarpa M, et al. European reference networks: challenges and opportunities. J Community Genet. 2021;12(2):217–29. https://doi.org/10.1007/s12687-021-00521-8 .

Austin CP, Cutillo CM, Lau LP, Jonker AH, Rath A, Julkowska D, et al. Future of rare diseases research 2017–2027: an IRDiRC perspective. Clin Transl Sci. 2018;11(1):21–7. https://doi.org/10.1111/cts.12500 .

Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources. Am J Hum Genet. 2009;84(4):524–33. https://doi.org/10.1016/j.ajhg.2009.03.010 .

Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36(10):928–30. https://doi.org/10.1002/humu.22844 .

Shafie AA, Chaiyakunapruk N, Supian A, Lim J, Zafra M, Hassali MAA. State of rare disease management in Southeast Asia. Orphanet J Rare Dis. 2016;11(1):1–11. https://doi.org/10.1186/s13023-016-0460-9 .

Baynam GS, Groft S, van der Westhuizen FH, Gassman SD, du Plessis K, Coles EP, et al. A call for global action for rare diseases in Africa. Nat Genet. 2020;52(1):21–6. https://doi.org/10.1038/s41588-019-0552-2 .

Hjorth E, Kreicbergs U, Sejersen T, Lövgren M. Parents’ advice to healthcare professionals working with children who have spinal muscular atrophy. Eur J Paediatr Neurol. 2018;22(1):128–34. https://doi.org/10.1016/j.ejpn.2017.10.008 .

Boulet L-P. The expert patient and chronic respiratory diseases. Canadian Respir J. 2016. https://doi.org/10.1155/2016/9454506 .

Prior L. Belief, knowledge and expertise: the emergence of the lay expert in medical sociology. Sociol Health Illn. 2003;25(3):41–57. https://doi.org/10.1111/1467-9566.00339 .

Rallison LB, Raffin-Bouchal S. Living in the in-between: families caring for a child with a progressive neurodegenerative illness. Qual Health Res. 2013;23(2):194–206. https://doi.org/10.1177/1049732312467232 .

Ballantine K, Gooder C, Ryan E, Macfarlane S. Listening to the experts: parents’ perspectives around infection risk and returning to education and social activities following their child’s diagnosis of acute lymphoblastic leukemia. Cancer Rep. 2021. https://doi.org/10.1002/cnr2.1424 .

Kish AM, Newcombe PA, Haslam DM. Working and caring for a child with chronic illness: a review of current literature. Child Care Health Dev. 2018;44(3):343–54. https://doi.org/10.1111/cch.12546 .

Pope AW, Tillman K, Snyder HT. Parenting stress in infancy and psychosocial adjustment in toddlerhood: a longitudinal study of children with craniofacial anomalies. Cleft Palate Craniofac J. 2005;42(5):556–9. https://doi.org/10.1597/04-066r.1 .

Jones TL, Prinz RJ. Potential roles of parental self-efficacy in parent and child adjustment: a review. Clin Psychol Rev. 2005;25(3):341–63. https://doi.org/10.1016/j.cpr.2004.12.004 .

Albanese AM, Russo GR, Geller PA. The role of parental self‐efficacy in parent and child well‐being: a systematic review of associated outcomes. Child Care Health Dev. 2019;45(3):333–63. https://doi.org/10.1111/cch.12661 .

Hjelmstedt S, Forinder U, Montgomery S, Lindahl Norberg A, Hovén E. Facilitators and barriers to return to work and meet financial needs in parents of children with cancer. Pediatr Blood Cancer. 2021;68(10): e29245. https://doi.org/10.1002/pbc.29245 .

Pauer F, Litzkendorf S, Göbel J, Storf H, Zeidler J, von der Schulenburg JMG. Rare diseases on the internet: an assessment of the quality of online information. J Med Internet Res. 2017;19(1):e23. https://doi.org/10.2196/jmir.7056 .

Titgemeyer SC, Schaaf CP. Facebook support groups for rare pediatric diseases: quantitative analysis. JMIR Pediatr Parent. 2020;3(2): e21694. https://doi.org/10.2196/21694 .

Feragen KB, Rumsey N, Heliövaara A, Boysen BM, Johannessen EC, Havstam C, et al. Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 9. Parental report of social and emotional experiences related to their 5-year-old child’s cleft diagnosis. J Plastic Surg Hand Surg. 2017;51(1):73–80. https://doi.org/10.1080/2000656X.2016.1254643 .

Whetten K, Leserman J, Whetten R, Ostermann J, Thielman N, Swartz M, et al. Exploring lack of trust in care providers and the government as a barrier to health service use. Am J Public Health. 2006;96(4):716–21. https://doi.org/10.2105/AJPH.2005.063255 .

Download references

Acknowledgements

We thank Marie Susanne Isachsen, librarian at the medical library at Oslo University Hospital, Rikshospitalet, Norway, for assistance in the search process.

Not applicable.

Author information

Authors and affiliations.

Centre for Rare Disorders, Rikshospitalet, Oslo University Hospital, P.B. 4950, 0424, Nydalen, Oslo, Norway

Charlotte von der Lippe, Ingrid Neteland & Kristin Billaud Feragen

You can also search for this author in PubMed   Google Scholar

Contributions

All authors have made substantial contributions to the manuscript. CvdL and KBF were responsible for the conception and design of the study. CvdL, IN, KBF collected data, performed the synthesis, and contributed in preparing the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Charlotte von der Lippe .

Ethics declarations

Ethics approval and consent to participate, consent for publication, competing interests.

The authors declare that they have no competing interests

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1.

. Appendix I.

Additional file 2

. Appendix II.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

von der Lippe, C., Neteland, I. & Feragen, K.B. Children with a rare congenital genetic disorder: a systematic review of parent experiences. Orphanet J Rare Dis 17 , 375 (2022). https://doi.org/10.1186/s13023-022-02525-0

Download citation

Received : 30 November 2021

Accepted : 02 October 2022

Published : 17 October 2022

DOI : https://doi.org/10.1186/s13023-022-02525-0

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

  • Rare genetic disorder
  • Parent experiences
  • Qualitative
  • Systematic review

Orphanet Journal of Rare Diseases

ISSN: 1750-1172

  • Submission enquiries: Access here and click Contact Us
  • General enquiries: [email protected]

genetic disorders research papers

ScienceDaily

Key genes linked to DNA damage and human disease uncovered

Scientists unveil 145 genes vital for genome health, and possible strategies to curb progression of human genomic disorders.

More than one hundred key genes linked to DNA damage have been uncovered through systematic screening of nearly 1,000 genetically modified mouse lines, in a new study published today (14 February) in Nature .

The work provides insights into cancer progression and neurodegenerative diseases as well as a potential therapeutic avenue in the form of a protein inhibitor.

The genome contains all the genes and genetic material within an organism's cells. When the genome is stable, cells can accurately replicate and divide, passing on correct genetic information to the next generation of cells. Despite its significance, little is understood about the genetic factors governing genome stability, protection, repair, and the prevention of DNA damage 1 .

In this new study, researchers from the Wellcome Sanger Institute, and their collaborators at the UK Dementia Research Institute at the University of Cambridge, set out to better understand the biology of cellular health and identify genes key to maintaining genome stability.

Using a set of genetically modified mouse lines, the team identified 145 genes that play key roles in either increasing or decreasing the formation of abnormal micronuclei structures 2 . These structures indicate genomic instability and DNA damage, and are common hallmarks of ageing and diseases.

The most dramatic increases in genomic instability were seen when the researchers knocked out the gene DSCC1 , increasing abnormal micronuclei formation five-fold. Mice lacking this gene mirrored characteristics akin to human patients with cohesinopathy disorders 3 , further emphasising the relevance of this research to human health.

Using CRISPR screening, researchers showed this effect triggered by DSCC1 loss could be partially reversed through inhibiting protein SIRT1 4 . This offers a highly promising avenue for the development of new therapies.

The findings help shed light on genetic factors influencing the health of human genomes over a lifespan and disease development.

Professor Gabriel Balmus, senior author of the study at the UK Dementia Research Institute at the University of Cambridge, formerly at the Wellcome Sanger Institute, said: "Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes, with the goal of improving outcomes and the overall quality of life for individuals across various conditions. Our study underscores the potential of SIRT inhibitors as a therapeutic pathway for cohesinopathies and other genomic disorders. It suggests that early intervention, specifically targeting SIRT1, could help mitigate the biological changes linked to genomic instability before they progress."

Dr David Adams, first author of the study at the Wellcome Sanger Institute, said: "Genomic stability is central to the health of cells, influencing a spectrum of diseases from cancer to neurodegeneration, yet this has been a relatively underexplored area of research. This work, of 15 years in the making, exemplifies what can be learned from large-scale, unbiased genetic screening. The 145 identified genes, especially those tied to human disease, offer promising targets for developing new therapies for genome instability-driven diseases like cancer and neurodevelopmental disorders."

  • Various sources of damage to the genome can include radiation, chemical exposure, and errors during DNA replication or repair processes.
  • Micronuclei are small abnormal structures, often referred to as "mutation factories," containing misplaced genetic material, that should otherwise be in the cell nucleus. Their presence signifies an increased risk of diseases like cancer and developmental disorders.
  • Cohesinopathy disorders are a group of genetic conditions resulting from dysfunctional cohesin proteins, essential for proper chromosome organisation and segregation during cell division. This can lead to a spectrum of developmental abnormalities, intellectual disability, distinctive facial features and growth retardation.
  • When the SIRT1 protein was suppressed, DNA damage reduced and they could rescue the negative effects of DSCC1 loss associated with cohesion disruption. This action was via restoring chemical levels of a protein called SMC3.
  • Human Biology
  • Personalized Medicine
  • Diseases and Conditions
  • Biotechnology
  • Biotechnology and Bioengineering
  • Genetically Modified
  • Human Genome Project
  • Human genome
  • DNA microarray
  • Gene therapy
  • Veterinary medicine
  • Dog skin disorders

Story Source:

Materials provided by Wellcome Trust Sanger Institute . Note: Content may be edited for style and length.

Journal Reference :

  • D. J. Adams, B. Barlas, R. E. McIntyre, I. Salguero, L. van der Weyden, A. Barros, J. R. Vicente, N. Karimpour, A. Haider, M. Ranzani, G. Turner, N. A. Thompson, V. Harle, R. Olvera-León, C. D. Robles-Espinoza, A. O. Speak, N. Geisler, W. J. Weninger, S. H. Geyer, J. Hewinson, N. A. Karp, Catherine L. Tudor, Angela L. Green, Cecilia Icoresi Mazzeo, Emma Siragher, Charlotte Lillistone, Diane Gleeson, Debarati Sethi, Tanya Bayzetinova, Jonathan Burvill, Bishoy Habib, Lauren Weavers, Ryea Maswood, Evelina Miklejewska, Michael Woods, Evelyn Grau, Stuart Newman, Caroline Sinclair, Ellen Brown, Brendan Doe, Antonella Galli, Ramiro Ramirez-Solis, Edward Ryder, Karen Steel, Allan Bradley, William C. Skarnes, David J. Adams, David Lafont, Valerie E. Vancollie, Robbie S. B. McLaren, Lena Hughes-Hallett, Christine Rowley, Emma Sanderson, Elizabeth Tuck, Monika Dabrowska, Mark Griffiths, David Gannon, Nicola Cockle, Andrea Kirton, Joanna Bottomley, Catherine Ingle, Chris Lelliott, Jacqueline K. White, B. Fu, F. Yang, Z. Kozik, J. Choudhary, L. Yu, M. S. van Ruiten, B. D. Rowland, C. J. Lelliott, M. del Castillo Velasco-Herrera, R. Verstraten, L. Bruckner, A. G. Henssen, M. A. Rooimans, J. de Lange, T. J. Mohun, M. J. Arends, K. A. Kentistou, P. A. Coelho, Y. Zhao, H. Zecchini, J. R. B. Perry, S. P. Jackson, G. Balmus. Genetic determinants of micronucleus formation in vivo . Nature , 2024; DOI: 10.1038/s41586-023-07009-0

Cite This Page :

  • Women's and Men's Brain Patterns Differ
  • A New Glue, Potentially Also for You
  • Excess Niacin Fuels Inflammation and CVD: Study
  • Measuring Neutrons to Reduce Nuclear Waste
  • 275 Million New Genetic Variants Identified
  • Astronomy: Radcliffe Wave Is Waving
  • Down Syndrome: Record in Ancient DNA
  • Smiling Is the Secret to Seeing Happiness
  • Women Get Benefits of Exercise With Less Effort
  • AI Computing at Light Speed?

Genetics of neurodegenerative diseases: an overview

Affiliations.

  • 1 Institute of Clinical Medicine, University of Oslo, Oslo, Norway; UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
  • 2 UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom; Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany.
  • 3 UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom. Electronic address: [email protected].
  • PMID: 28987179
  • DOI: 10.1016/B978-0-12-802395-2.00022-5

Genetic factors are central to the etiology of neurodegeneration, both as monogenic causes of heritable disease and as modifiers of susceptibility to complex, sporadic disorders. Over the last two decades, the identification of disease genes and risk loci has led to some of the greatest advances in medicine and invaluable insights into pathogenic mechanisms and disease pathways. Large-scale research efforts, novel study designs, and advances in methodology are rapidly expanding our understanding of the genome and the genetic architecture of neurodegenerative disease. Here, we review major developments in the field to date, highlighting overarching historic trends and general insights. Monogenic neurodegenerative diseases are discussed from the perspectives of both rare Mendelian forms of common disorders, such as Alzheimer disease and Parkinson disease, and heterogeneous heritable conditions, including ataxias and spastic paraplegias. Next, we summarize the experiences from investigations of complex neurodegenerative disorders, including genomewide association studies. In the final section, we reflect upon the limitations of current findings and outline important future directions. Genetics plays an essential role in translational research, ultimately aiming to develop novel disease-modifying therapies for neurodegenerative disorders. We anticipate that individual genetic profiling will also be increasingly relevant in a clinical context, with implications for patient care in line with the proposed ideal of personalized medicine.

Keywords: Alzheimer's diseases; Genetics; Parkinson's disease; genome-wide association study (GWAS); neurodegeneration.

Copyright © 2017 Elsevier B.V. All rights reserved.

Publication types

  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / physiopathology

Grants and funding

  • G0802760/MRC_/Medical Research Council/United Kingdom
  • G1001253/MRC_/Medical Research Council/United Kingdom
  • G108/638/MRC_/Medical Research Council/United Kingdom
  • MR/J004758/1/MRC_/Medical Research Council/United Kingdom
  • Introduction to Genomics
  • Educational Resources
  • Policy Issues in Genomics
  • The Human Genome Project
  • Funding Opportunities
  • Funded Programs & Projects
  • Division and Program Directors
  • Scientific Program Analysts
  • Contact by Research Area
  • News & Events
  • Research Areas
  • Research investigators
  • Research Projects
  • Clinical Research
  • Data Tools & Resources
  • Genomics & Medicine
  • Family Health History
  • For Patients & Families
  • For Health Professionals
  • Jobs at NHGRI
  • Training at NHGRI
  • Funding for Research Training
  • Professional Development Programs
  • NHGRI Culture
  • Social Media
  • Broadcast Media
  • Image Gallery
  • Press Resources
  • Organization
  • NHGRI Director
  • Mission & Vision
  • Policies & Guidance
  • Institute Advisors
  • Strategic Vision
  • Leadership Initiatives
  • Diversity, Equity, and Inclusion
  • Partner with NHGRI
  • Staff Search

Genetic Disorders

Many human diseases have a genetic component. Some of these conditions are under investigation by researchers at or associated with the National Human Genome Research Institute (NHGRI).

A genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence. Genetic disorders can be caused by a mutation in one gene (monogenic disorder), by mutations in multiple genes (multifactorial inheritance disorder), by a combination of gene mutations and environmental factors, or by damage to chromosomes (changes in the number or structure of entire chromosomes, the structures that carry genes). As we unlock the secrets of the human genome (the complete set of human genes), we are learning that nearly all diseases have a genetic component. Some diseases are caused by mutations that are inherited from the parents and are present in an individual at birth, like sickle cell disease. Other diseases are caused by acquired mutations in a gene or group of genes that occur during a person's life. Such mutations are not inherited from a parent, but occur either randomly or due to some environmental exposure (such as cigarette smoke). These include many cancers, as well as some forms of neurofibromatosis.

List of Genetic Disorders

This list of genetic, orphan and rare diseases is provided for informational purposes only and is by no means comprehensive.

About Achondroplasia | NHGRI

Featured Content

Person (icon) circled

Last updated: May 18, 2018

  • U.S. Department of Health & Human Services

National Institutes of Health (NIH) - Turning Discovery into Health

  • Virtual Tour
  • Staff Directory
  • En Español

You are here

News releases.

News Release

Tuesday, February 20, 2024

Researchers optimize genetic tests for diverse populations to tackle health disparities

Improved genetic tests more accurately assess disease risk regardless of genetic ancestry.

To prevent an emerging genomic technology from contributing to health disparities, a scientific team funded by the National Institutes of Health has devised new ways to improve a genetic testing method called a polygenic risk score . Since polygenic risk scores have not been effective for all populations, the researchers recalibrated these genetic tests using ancestrally diverse genomic data. As reported in Nature Medicine , the optimized tests provide a more accurate assessment of disease risk across diverse populations.

Genetic tests look at the small differences between individuals’ genomes, known as genomic variants , and polygenic risk scores are tools for assessing many genomic variants across the genome to determine a person’s risk for disease. As the use of polygenic risk scores grows, one major concern is that the genomic datasets used to calculate the scores often heavily overrepresent people of European ancestry.

“Recently, more and more studies incorporate multi-ancestry genomic data into the development of polygenic risk scores,” said Niall Lennon, Ph.D., a scientist at the Broad Institute in Cambridge, Massachusetts and first author of the publication. “However, there are still gaps in genetic ancestral representation in many scores that have been developed to date.”

These “gaps” or missing data can cause false results, where a person could be at high risk for a disease but not receive a high-risk score because their genomic variants are not represented. Although health disparities often stem from systemic discrimination, not genetics, these false results are a way that inequitable genetic tools can exacerbate existing health disparities.

In the new study, the researchers improved existing polygenic risk scores using health records and ancestrally diverse genomic data from the All of Us Research Program, an NIH-funded initiative to collect health data from over a million people from diverse backgrounds.

The All of Us dataset represented about three times as many individuals of non-European ancestry compared to other major datasets previously used for calculating polygenic risk scores. It also included eight times as many individuals with ancestry spanning two or more global populations. Strong representation of these individuals is key as they are more likely than other groups to receive misleading results from polygenic risk scores.

The researchers selected polygenic risk scores for 10 common health conditions, including breast cancer, prostate cancer, chronic kidney disease, coronary heart disease, asthma and diabetes. Polygenic risk scores are particularly useful for assessing risk for conditions that result from a combination of several genetic factors, as is the case for the 10 conditions selected. Many of these health conditions are also associated with health disparities.

The researchers assembled ancestrally diverse cohorts from the All of Us data, including individuals with and without each disease. The genomic variants represented in these cohorts allowed the researchers to recalibrate the polygenic risk scores for individuals of non-European ancestry.

With the optimized scores, the researchers analyzed disease risk for an ancestrally diverse group of 2,500 individuals. About 1 in 5 participants were found to be at high risk for at least one of the 10 diseases.

Most importantly, these participants ranged widely in their ancestral backgrounds, showing that the recalibrated polygenic risk scores are not skewed towards people of European ancestry and are effective for all populations.

“Our model strongly increases the likelihood that a person in the high-risk end of the distribution should receive a high-risk result regardless of their genetic ancestry,” said Dr. Lennon. “The diversity of the All of Us dataset was critical for our ability to do this.”

However, these optimized scores cannot address health disparities alone. “Polygenic risk score results are only useful to patients who can take action to prevent disease or catch it early, and people with less access to healthcare will also struggle to get the recommended follow-up activities, such as more frequent screenings,” said Dr. Lennon.

Still, this work is an important step towards routine use of polygenic risk scores in the clinic to benefit all people. The 2,500 participants in this study represent just an initial look at the improved polygenic risk scores. NIH’s Electronic Medical Health Records and Genomics (eMERGE) Network will continue this research by enrolling a total of 25,000 participants from ancestrally diverse populations in the study’s next phase.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Connect with Us

  • More Social Media from NIH

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • View all journals
  • Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • Published: 14 March 2022

Rare diseases, common challenges

Nature Genetics volume  54 ,  page 215 ( 2022 ) Cite this article

10k Accesses

7 Citations

9 Altmetric

Metrics details

  • Clinical genetics
  • Medical research

The genetics community has a particularly important part to play in accelerating rare disease research and contributing to improving diagnosis and treatment. Innovations in sequencing technology and machine learning approaches have positively affected diagnostic success, but more coordinated efforts are needed to move towards effective therapies or even cures for these important, and sometimes overlooked, class of diseases.

Rare Disease Day was recently held on 28 February 2022, which aimed to raise awareness and promote advocacy for rare disease research. Globally, there are more than 300 million people living with rare diseases and there are no approved therapies for over 90% of these disorders. Because around 80% of rare diseases have a genetic basis, recent advances in genomic sequencing technologies and molecular gene therapies have enhanced diagnosis and expanded treatments. To ensure that these advances are benefitting as many patients as possible and doing so in an equitable manner, unified efforts that span different stakeholders across rare disease communities should be supported.

In this issue of Nature Genetics , Halley and colleagues present a Comment that calls for an integrated approach for rare disease research in the United States. The authors argue that rare diseases are an important public health issue that should be given commensurate attention for their collective effects on individual patients, disease communities and healthcare systems. As such, the approach to rare disease research needs to broader for maximum benefits to a greater number of patients. The authors call for integrated approaches to research infrastructure that would minimize barriers to making connections, whether biological, therapeutic or societal, within and between rare diseases.

The authors highlight that rare disease research is currently very siloed and often organized around single disorders. Although efforts such as the Rare Disease Clinical Research Network have taken a broader approach, overall, there is limited coordination across rare disease research networks. The single-disorder focus creates challenges for jointly combining efforts, sharing data, assessing outcomes and capturing knowledge that could be relevant across diseases. A more integrated structure with appropriate support for researchers to coordinate across rare diseases would minimize redundant efforts and increase efficiency, potentially accelerating development and the implementation of successful therapies.

Importantly, no recommendations intended to promote rare disease research can ignore equity; indeed, ensuring fair practices in funding and equitable benefits of research outcomes must be a central focus of any research initiatives into rare diseases. It is challenging to achieve greater parity across rare diseases within the current research infrastructure, as analyzing how outcomes vary within or across rare diseases in different populations or socioeconomic groups is not straightforward. A more integrated approach to rare disease research will enable the assessment of how various factors (such as income level, insurance status, or racism in health care) affect participation in rare disease research or access to its benefits.

Altogether, the authors advocate for moving towards a more coordinated approach to rare disease research that would enable analysis of the similarities and differences across diseases in terms of etiology, treatment and outcomes. Although this article is specifically focused on the United States, the authors also recognize existing international efforts, such as the Global Genes and Genetic Alliance and the International Rare Disease Research Consortium that are leading the way in facilitating coordinated research efforts and data sharing.

We are excited by new technical advances in rare disease genetics research that apply the latest technologies to improve diagnosis. As an example, also in this issue of Nature Genetics , Hsieh and colleagues report a tool that uses deep convolutional neural networks to aid in diagnosing ultra-rare disorders based on facial morphology. GestaltMatcher defines a Clinical Face Phenotype Space based on over 17,000 photographs of patients representing more than 1,100 rare disorders. An advantage of using this method is that patients who share the same genetic diagnosis can be matched, even in cases when the disorder is not part of the training set. This helps with the clinical diagnosis of both known and new phenotypes. The concept of matching patients with rare disease is also conveyed on our cover, with actual matches forming the shape of a human face.

Rare disease research encompasses passionate individuals who span different sectors of interest: clinicians, patients, genetic counselors, biologists, technicians, advocates, funders and educators. We hope that the common challenges facing rare disease research can be combatted through enhanced coordination and cooperation across research communities, with the goal of accelerating diagnosis, maximizing therapeutic benefits and reducing inefficiencies.

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Rare diseases, common challenges. Nat Genet 54 , 215 (2022). https://doi.org/10.1038/s41588-022-01037-8

Download citation

Published : 14 March 2022

Issue Date : March 2022

DOI : https://doi.org/10.1038/s41588-022-01037-8

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Highly efficient capture approach for the identification of diverse inherited retinal disorders.

  • Hsiao-Jung Kao
  • Ting-Yi Lin
  • Shun-Ping Huang

npj Genomic Medicine (2024)

Quick links

  • Explore articles by subject
  • Guide to authors
  • Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

genetic disorders research papers

Daily Mail

NIH study uncovers 275MILLION entirely new genetic variants that may explain why some Americans are prone to diseases like cancer and diabetes

  • Researchers in $3billion NIH-led study analyzed genomes of 245,000 Americans
  • At least four million of the new variants are thought to affect people's health
  • READ MORE: Rare genetic variants protect against obesity, says study

More than 275million entirely new genetic variants have been discovered in humans — and some of them could reveal a higher risk of cancer  or diabetes.

Researchers led by the National Institute of Health (NIH) in Bethesda, Maryland , revealed the findings after studying a giant database containing the genomes of 245,000 Americans, around half of whom were from minority backgrounds.

Most of the variants had no effect on health, the researchers said, but nearly 4million were found in genes linked to a higher risk of cancer, diabetes and heart disease — among other conditions.

Dr Josh Denny, the lead author of the study, said: 'Sequencing diverse populations can lead to new drug targets that are relevant to everyone.

'It can also help uncover disparities that lead to specific treatments for people that are experiencing higher burdens of disease or different disease.'

The research is part of the All of Us program, a $3.1billion national project aiming to 'bridge the gap' in genetic studies — which tend to focus on populations from white backgrounds.

Nearly 90 percent of genetic studies to date have been focused on white populations, estimates suggest. But this project aims to shift the balance by assessing the health profiles of a million Americans, including half a million from minority backgrounds.

Finding new genotypes in minority populations can help to reveal genetic variants leaving someone more prone to disease — or in the development and discovery of new drugs to treat conditions like high cholesterol.

The All of Us program was launched in 2018 — and by April 2023 had more than 440,000 adults signed up, with the project set to run until 2026.

The latest figures — revealed in a package published by Nature, Communications Biology and Nature Medicine — are based on 250,000 people, with researchers aiming to quadruple this number to a million.

Dr Alicia Martin, a population geneticist at Massachusetts General Hospital in Boston, said the project was a 'huge resource, particularly for African American, Hispanic and Latin American genomes'.

'That's massively missing from the vast majority of large-scale biobank resources and genomics consortia,' she added to Nature .

In one of the papers, of which nearly 40 percent of participants were from minority backgrounds, researchers found 611 genetic markers that could raise the risk of suffering from diabetes — 145 of which had not been previously reported.

They said the new variants could help to 'inform diabetes care', particularly for adults from minority backgrounds.

In another of the studies, researchers looked at pathogenic genetic variants — or those that raise the risk of certain diseases such as cancer.

Results revealed people with European ancestry have about 2.3 percent of their genome made up of pathogenic variants, on average, while among those with African ancestry, this drops to 1.6 percent.

Recent studies have already shown how genetic diversity can impact disease risk. 

Variants in the APOL1 gene discovered in 2010 help account for 70 percent of the increased risk for chronic kidney disease and dialysis seen in people in the U.S. with sub-Saharan African ancestry.

Likewise, a class of drugs called PCSK9 inhibitors that dramatically lower very high levels of low-density lipoprotein (LDL) — the so-called bad cholesterol — were discovered by sequencing the genetic code of 5,000 people in Dallas of African ancestry.

Much more work is needed to understand how the new trove of genetic variants contributes to various health conditions, but the scientists believe they could be used to refine tools used to calculate a person's risk for disease.

MailOnline logo

U.S. flag

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

  • Publications
  • Account settings
  • Advanced Search
  • Journal List
  • Dialogues Clin Neurosci
  • v.20(3); 2018 Sep

Language: English | Spanish | French

The role of genetics and genomics in clinical psychiatry

El papel de la genética y de la genómica en la psiquiatría clínica, rôles de la génétique et de la génomique en psychiatrie clinique, margret r. hoehe.

Max-Planck Institute for Molecular Genetics, Berlin, Germany

Deborah J. Morris-Rosendahl

Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, London, UK, NHLI, Imperial College London, UK

The enormous successes in the genetics and genomics of many diseases have provided the basis for the advancement of precision medicine. Thus, the detection of genetic variants associated with neuropsychiatric disorders, as well as treatment outcome, has raised growing expectations that these findings could soon be translated into the clinic to improve diagnosis, the prediction of disease risk and individual response to drug therapy. In this article, we will provide an introduction to the search for genes involved in psychiatric illness and summarize the present findings in major psychiatric disorders. We will review the genetic variants in genes encoding drug metabolizing enzymes and specific drug targets which were found to be associated with variable drug response and severe side effects. We will evaluate the clinical translatability of these findings, whether there is currently any role for genetic testing and in this context, make valuable sources of information available to the clinician seeking guidance and advice in this rapidly developing field of psychiatric genetics.

Los enormes éxitos en la genética y la genómica de muchas enfermedades han proporcionado la base para el avance de la medicina de precisión. Por lo tanto, la detección de variantes genéticas asociadas con trastornos neuropsiquiátricos, así como el resultado del tratamiento, han aumentado las expectativas que estos hallazgos pronto podrían traducirse en la clínica para mejorar el diagnóstico, la predicción de riesgo de enfermar y la respuesta individual a la terapia farmacológica. En este artículo, se presentará una introducción sobre la búsqueda de genes implicados en enfermedades psiquiátricas y se resumirán los hallazgos actuales en los principales trastornos psiquiátricos. Se revisarán las variantes genéticas para genes que codifican enzimas metabolizadoras de fármacos y los blancos farmacológicos específicos que se encontraron asociados con una respuesta farmacológica variable y efectos secundarios graves. Se evaluará la traducción clínica de estos hallazgos, la posibilidad actual de algún papel para las pruebas genéticas y, en ese contexto, se pondrá a disposición del clínico que busca guía y consejo, valiosas fuentes de información para este campo de rápido desarrollo que es la psiquiatría genética.

Les énormes succès obtenus en génétique et génomique dans de nombreuses maladies ont fourni la base des avancées en médecine de précision. La détection de variants génétiques, associés à des troubles neuro-psychiatriques comme à des résultats thérapeutiques, a donc soulevé une attente grandissante de voir traduire ces résultats en pratique clinique pour améliorer le diagnostic, la prédiction du risque d'avoir la maladie et la réponse individuelle au traitement médicamenteux. Nous introduisons dans cet article la recherche de gènes impliqués en pathologie psychiatrique et nous résumons les résultats actuels pour les principaux troubles psychiatriques. Nous analysons les variants génétiques des gènes codant pour les enzymes métabolisant les médicaments et les cibles médicamenteuses spécifiques ayant montré une association avec une réponse variable au médicament et des effets indésirables sévères. Nous évaluons la traduction de ces résultats en pratique clinique, la possibilité actuelle d'un rôle du dépistage génétique et, dans ce contexte, la mise à disposition du médecin en recherche d'aide et de conseils, de sources valables d'information dans ce domaine en rapide développement qu'est la psychiatrie génétique.

The search for genes underlying psychiatric illness

For decades, researchers have intensively sought to identify the underlying molecular causes of psychiatric illness. Understanding the biology of the disease, they believed, would enable valid clinical diagnosis and risk prediction, as well as a better treatment of the individual. So from the 1960s, the biological hypotheses for psychiatric diseases were focused primarily on the catecholamine and indoleamine neurotransmitter systems, which were tested by use of indirect strategies, such as neuroendocrinological challenges, as “windows to the brain.” From the mid-1980s, family, twin, and adoption studies have provided consistent evidence for aggregate genetic effects for psychiatric disorders, demonstrating the substantial role of genetic factors in the etiology of mental illness. 1 The heritability estimates for most psychiatric disorders were found to be high, between 0.4 and 0.8. 2 These results motivated efforts to search for molecular genetic variants predisposing to psychiatric disease. The first-generation molecular genetic studies were, however, largely unsuccessful. Genetic linkage studies of psychiatric disease, pre-assuming existence of single major loci or few large-effect genes, produced mostly negative or irreproducible results. Candidate gene association studies primarily focusing on synthetic, degradative, and receptor components of neurotransmitter systems proved controversial. 1 , 3

The release of a working draft of human genome sequence in 2000 marked the beginning of a new era, with enormous progress in the development of increasingly more efficient sequencing and genotyping technologies allowing the assessment of human genetic variation genome-wide, systematically, and much more completely. Exome- and genome-wide analysis in substantial numbers of individuals became feasible. Genome -wide association studies (GWAS) evolved as a key tool to identify genetic risk variants related to complex disease. This “reverse genetics” approach facilitated the identification of potentially pathogenic variants never previously conceived of, without prior pathophysiological hypothesis. Moreover, statistical methods were developed that allowed assessment of the aggregate effects of genome-wide DNA variation captured by GWAS, 1 for instance by calculating the joint contribution of common variants as a “polygene score.” 4 Finally, progress in psychiatric genetics would have been impossible without the international community combining data sets across multiple GWAS studies to maximize sample size (projecting for instance 100 000 cases for schizophrenia by 2019) and statistical power. 5 So from 2011, replicated common SNPs began to emerge from the GWAS of major psychiatric disorders, beginning with schizophrenia 6 and bipolar disorder. 7 By far the strongest GWAS signal was the association between schizophrenia and genetic markers across the Major Histocompatibility Complex (MHC) locus on chromosome 6. Through very careful molecular dissection of this complex locus, the signal on chromosome 6 was traced to the C4 gene. 8 It has been suggested that increased C4 activity in the brain of people with schizophrenia causes excessive synaptic pruning during postnatal brain development. 8 If this is supported by further work, it is one of very few times that the underlying biological process has been revealed from a GWAS signal.

Mostly facilitated by data from high density genomic arrays used in GWAS, large de novo and rare chromosomal deletions and duplications, so-called copy number variants (CNVs), began to be identified, that substantially increase risk for psychiatric disorders, especially autism spectrum disorder 9 , 10 and schizophrenia 11 , 12 but also other conditions such as attention-deficit hyperactivity disorder (ADHD). 13 Whole-exome sequencing (WES), the high throughput sequencing of all coding exons in the human genome, resulted in first (replicated) discoveries of de novo (gene-disrupting) coding mutations in autism spectrum disorder 14 - 17 and schizophrenia. 18 - 20

Taken together, the emerging architecture of psychiatric disease was found to be highly polygenic, with hundreds or even thousands of common variants of small effect size (with 1.1% to 1.2% absolute risk of illness compared with a -1.0% population risk), accounting collectively for about one third to one half of the heritability between 0.4 and 0.8. 2 Such a polygenic picture is typical for most complex traits. In addition, rare and de novo CNVs with large effect size (odds ratio ~2 to >20) as well as rare and de novo (disrupting) variants can significantly contribute to risk for major psychiatric disorders. The overall contribution of these types of variants is, however, less well understood.

There is increasing evidence for an etiological overlap between major psychiatric disorders, which would in many, though not all, instances have been predicted from their clinical presentation. 2 Major psychiatric disorders have been found to share common genetic variation, 5 , 21 , 22 with the first GWAS meta-analyses implicating neuronal/synaptic, immune and histone pathways. 23 Similarly, an overlap has been observed for rare and de novo CNVs 24 and other coding mutations. 19 , 20 The substantial overlap of genetic risk between the disorders reinforces evidence for comorbidity from earlier genetic epidemiological studies, as exemplified by an increased risk for different psychiatric disorders in relatives of a patient. 5 A recent, elegant study 25 using transcriptomic profiling in the cerebral cortex across autism, schizophrenia, bipolar disorder, depression and alcoholism, revealed patterns of shared and distinct gene-expression perturbations across these disorders. Their data suggested that common polygenic variation underlies a substantial proportion of cross-disorder expression overlap. These results underscore that psychiatric disorders as “clinical-historical constructs” 1 do not correspond to distinct definable pathophysiological entities 1 and question the value of clinical diagnostic stratification and classification.

Translating genetic findings to clinical practice

The enormous successes in genomic medicine, with the dramatic increase in the number of established gene-disease relationships for Mendelian disorders and the distinction of individual molecular tumor profiles in cancer allowing individualized diagnosis and treatment, have motivated efforts to advance precision medicine. These developments have been spurred mainly by the dramatic technological advances of the past 7 years with the implementation of next-generation sequencing (NGS) and all that it has enabled. Whereas genetic testing prior to NGS was performed primarily for very rare, single gene disorders, many of which had recurrent mutations, the advent of NGS has allowed the simultaneous interrogation of many genes and all their variants, using either targeted gene panels, WES, or whole genome sequencing (WGS).The detection of replicated genetic variants associated with neuropsychiatric disorders and treatment outcome has raised growing expectations that these results could be translated into the clinic, to improve individual diagnosis and the prediction of individual risk and treatment response, as well as predict the risk for other family members. Comprehensive genetic tests have become available, and are also commercially provided to doctors and individuals, not least by “direct-to-consumers” (DTC) testing. Thus, it is time to address the potential clinical relevance of genetic testing in psychiatry.

Prerequisites for genetic testing are analytic validity (does the test accurately detect whether a specific genetic variant is present or absent), and clinical validity (is there adequate scientific evidence to support the correlation between the genetic variant and a specific disease phenotype or risks?). Replication is critical for clinical validity. Clinical utility refers to whether the test can “provide information about diagnosis, treatment, management, or prevention of a disease that is likely to improve patient outcomes” (https://ispg.net/genetic-testing-statement/; http://www.cdc.gov/genomics/gtesting/ACCE/index.htm.). The essential prerequisite is knowledge of the genetic causes of the disorder and robust genotype-phenotype correlations, to enable for instance predictive testing for later onset disorders for family members of affected patients.

As outlined above, major adult psychiatric disorders are generally not caused by a single gene or variant, nor do they have a rare Mendelian subform as many other complex disorders do, eg, the adult-onset neurodegenerative disorders such as Alzheimer disease. On the contrary, they are complex, highly polygenic disorders involving numerous genes and variants that have only a modest impact on risk and are neither necessary nor sufficient to cause disease. This makes a clinical interpretation of the present findings at the individual level extremely difficult, if not impossible. Thus, despite tremendous progress in recent years, psychiatric genetics has, with few exceptions, not yet sufficiently advanced to be able to deduce concrete recommendations, or even clinical guidelines, for the use of genetic testing for diagnostic purposes and risk prediction. This applies in particular to major psychiatric disorders which typically begin in adult life, such as depression, bipolar disorder, substance dependence, and schizophrenia (see also https://ispg.net/genetic-testing-statement/; the 'Genetic Testing Statement' of the International Society of Psychiatric Genetics (ISPG) is being periodically updated as research progresses).

There are, however, a few circumstances where genetic testing may be useful in various clinical settings. These pertain to the analysis of variants of strong effect, such as rare or de novo CNVs and disrupting mutations, prevalent in individuals with autism spectrum disorders (ASD), schizophrenia, or other psychiatric disorders, especially when accompanied by intellectual disability. ASD not only has shared phenotypic overlap with many syndromic forms, such as Down syndrome, Prader-Willi/Angelman syndrome and Fragile X-linked intellectual disability (about 4% to 5% of ASD), 26 but is also one of the disorders for which rare variants have been demonstrated to have strong effect. The potential detection of such rare variants has made it amenable to genetic testing in one form or another. Microdeletion 22qll.l syndrome is typically caused by a recurrent 3 MB deletion of 40 genes, including TBX1. Twenty to 50% of patients with this deletion develop ASD, 27 but the deletion is also found in approximately 1% of people with schizophrenia and also in patients with bipolar disorder and idiopathic Parkinson disease. 28 , 29 Current microarrays detect an ASD-associated CNV in 7% to 10 % of cases. 30 There are now more than 50 ASD-associated CNVs and at least 61 ASD-risk genes, 18 of which have recently been identified in a comprehensive study using WGS of trios. 31 Of the 61 ASD-associated genes, 36 (59%) are associated with known syndromes/ phenotypes in OMIM (Online Mendelian Inheritance in Man, www.omim.org), with CHD8, SHANK2, and NLGN3 associated only with ASD. Many of the identified ASD-risk genes converge into shared biological pathways and networks, including synaptic and neuronal adhesion (SHANK3, SCN2A, GRIN2B, SYNGAP1, ANK2), axonal guidance, transcriptional regulation (eg, NF1, PTEN and SYNGAP1) and chromatin remodeling (eg, MECP2, MBD5, CHD8, ADNP, ARID1B and TBR1)? 1 , 32 Sixteen genes contain subdomains that could be targeted by pharmaceutical interventions and specific drug-gene interactions are known for seven genes. 31 For example, individuals with pathogenic variants in SCN2A are potential candidates for drug trials involving allosteric modulators of GABA receptors. 33

Multiple, rare CNVs have been associated with schizophrenia, all of which encompass many genes and are also common to other psychiatric and neurological disorders. 34 Approximately 2.5% of schizophrenia patients will carry one of the associated CNVs, and many more genes may be associated through more powerful sequencing studies in the near future. 35 The use of patient-parent trios to identify potentially harmful “de novo” variants has been applied to schizophrenia in a number of studies. 18 - 20 , 36 Each of these studies demonstrated an excess of damaging de novo variants in schizophrenia, particularly in glutamatergic postsynaptic proteins and proteins whose messenger RNAs are targets of the Fragile X-linked mental retardation protein, FMRP. A subsequent, combined whole-exome sequencing case-control analysis in 4264 patients, 9343 controls and 1077 trios from previous studies revealed a significant excess of very rare, gene-disrupting variants in the SETD1A gene in patients (0.19%). This was the first statistically significant association between schizophrenia and a single candidate gene, 37 although pathogenic SETD1A variants are also found in patients with more severe developmental and physical abnormalities. SETDIA is involved in histone methylation, substantiating the report that common risk variants for psychiatric disorders may aggregate on histone methylation pathways. 23

Although individually rare, the net effects of CNVs across psychiatric disorders are substantial. Specifically, the net effects of the more frequent CNVs on a broad range of psychiatric and intellectual disability- syndromes have already been sufficiently well-assessed by Malhotra et al 38 and Gershon and Alliey-Rodriguez. 39 A recent review of CNVs in schizophrenia in over 41 000 subjects by Marshall et al 34 largely confirmed previous reports of CNV associations in schizophrenia, adding suggestive evidence for six novel CNVs and providing analyses of the genes involved and of the net effects of these CNVs on schizophrenia. Although the majority of adult patients would not be expected to carry a large CNV and such CNVs mostly lack diagnostic specificity-, the identification of an inherited or de novo CNV in a known high-risk region for one of the major psychiatric disorders in such patients, may help diagnose a rare condition that has important medical and psychiatric implications for the patient and their family. Patients who carry such CNVs may find it easier to accept their diagnosis and adhere to treatment when presented with an objective “laboratory test.” 39 Siblings and offspring could be offered genetic testing and might be reassured if they do not carry the same CNV as their mentally ill relative; 39 (https://ispg.net/genetic-testing-statement/). The identification of de novo CNVs could be useful in the management of severe psychiatric disorders, especially those that present atypically or in the context of intellectual disability or certain medical syndromes (https://ispg.net/genetic-testing-statement/) .

The analysis of genes involved in variable drug response

The pharmacological treatment of psychiatric disorders has been severely hampered by a large inter-individual variation in drug response and/or severe side effects, often leading to painful, frustrating and inefficient trial-and-error-based changes of treatment regimens. This variation is to a large extent due to genetic factors, with an estimated heritability h 2 of ~0.6 - 0.8. 40 Thus, numerous studies attempted to detect gene variants associated with individually different drug responsiveness or serious side effects. Their motivation was to identify pharmacogenetic biomarkers for drug efficacy and safety, which would allow prediction of an individual's response to drug therapy and facilitate individually tailored treatment. These studies focused primarily on the analysis of candidate genes including (i) genes involved in drug metabolism (pharmacokinetics); (ii) genes encoding the specific target molecules mediating drug action (pharmacodynamics); and (iii) genes mediating severe side effects. Typically, a few up to hundreds of SNPs within these genes were genotyped in cases and controls. Furthermore, GWAS were applied to scan the genome for variants predisposing to differential drug response “hypothesis-free,” allowing detection of yet unknown genes or biological mechanisms. In view of the immense literature, we will prioritize those results which proved to be most consistent and therefore merit further consideration for potential translation in the clinic. We will focus on the pharmacogenomics of antidepressants and antipsychotics. The results essentially refer to drug-gene relationships.

Two genes of central importance in the metabolism of antidepressants and antipsychotics are those encoding cytochrome P450 (CYP) monooxygenase system enzymes, CYP2D6 and CYP2C19. 41 , 42 Variants in these genes can cause different pharmacokinetic phenotypes in individuals treated with the same dose of a drug: “ultrarapid metabolizers” (UM), characterized by significantly- reduced drug concentrations, hence decreased drug effect or non-response; “extensive metabolizers” (EM) representing the “normal” phenotype; “intermediate metabolizers” (IM), characterized by drug concentrations that are higher compared to EM; and “poor metabolizers” (PM) having the highest drug concentrations at all, resulting potentially in drug-related toxicity due to overdosing. 41 Thus, UM and PM appear to represent the clinically most relevant phenotypes/genotypes. In effect, comprehensive systematic literature reviews have substantiated evidence for lower plasma levels and an increased risk for non-response to tricyclic antidepressant treatment in UM as well as an increased risk for severe side effects in PM. 43 - 45 The same applied to antidepressant treatment with selective serotonin reuptake inhibitors (SSRI). 43 , 46 Regarding treatment with antipsychotics, the studies show a significantly increased risk for tardive dyskinesias in particular for CYP2D6-PM, while CYP2D6-UM overall does not appear to have a significant influence on antipsychotic drug response. Furthermore, a potential influence of CYP1A2 and CYP3A4 variants, other pharmacokinetic candidates of importance, on antipsychotic response has remained inconclusive. 40 , 42 , 43 , 45 Importantly, the altered activity CYP2D6 variants have been reported to exhibit substantial population differences in comprehensive global surveys. 47 - 49 Based on the first global data, 48 Europeans showed the highest fraction of CYP2D6-PM (8%) and ~3% CYP2D6-UM, while for instance 40% of the population were CYP2D6-UM in North Africa. Thus, knowledge of ethnic background is of critical clinical relevance for the development of personalized pharmacological treatment strategies. The classification of pharmacokinetic phenotypes described above is subject to constant efforts towards further standardization. Although well-established, it does not yet represent the entirety- of genetic variation, or allelic combinations. A meta-analysis of population scale sequencing projects integrating whole-genome and exome NGS data from 56 945 individuals of five major populations, demonstrated that the previous pharmacokinetic phenotype predictions from genotype data may have underestimated the prevalence of CYP2D6-PM and -IM subjects substantially. 49 Between 25.3% and 70.3% of analyzed CYP alleles contained variant combinations with no or reduced functional activity. This trend was further substantiated in a comprehensive literature review. 47 Another gene of potential importance for the pharmacokinetics of many antidepressants and some antipsychotics encodes the ATP Binding Cassette (ABC) Subfamily B Member 1 (ABCB1); this ABC transporter gene is expressed at blood-brain barrier (BBB) sites. Its membrane-associated gene product, P Glycoprotein, also known as Multidrug-Resistance Protein 1, transports various substances across the BBB out of the brain. Meta-analyses have shown associations of two (out of several) SNPs with antidepressant response. 50 , 51 Overall, however, the role of genetic variation in ABCB1 in variable antidepressant response has remained controversial and will require further examination.

Concerning the analysis of pharmacodynamic candidate genes involved in antidepressant response, a large number of studies have addressed the gene encoding the serotonin transporter (SCL6A4), a direct target for most prescribed antidepressants. The functional insertion-deletion polymorphism located in the promoter region, 5-HTTLPR, possibly was the most studied variant in relation to antidepressant response at all. Significant associations between this polymorphism and antidepressant response and remission rates were described in major meta-analyses. 52 , 53 Particularly-, a higher probability of response and remission to SSRI treatment was observed in Caucasian carriers of the long (“1”) allele, although its influence on SSRI efficacy was of modest effect. 52 Inversely, Caucasian patients with the short (“s”) allele were found to have difficulties to achieve remission and showed a reduced response to SSRI 52 , 53 as well as an increased risk for side effects. 54 Overall, however, the results are still inconsistent, precluding the use of 5-HTTLPR as a predictor of antidepressant response at present. 42 Condensing other candidate gene data of note, a comprehensive meta-analysis by 51 has suggested a significant association of variants in the serotonin 2A receptor gene (HTR2A) with antidepressant response; the same was true for variants in the gene encoding the FK506-binding protein 5 (FKBPS), which is involved in the regulation of stress hormones. Furthermore, this meta-analysis substantiated evidence that heterozygous carriers of the rs6265 polymorphism (Val66Met) in the brain-derived neurotrophic factor gene (BDNF) respond best to SSRI, particularly Asian patients. 51 Numerous other plausible candidate genes have been investigated, with controversial results and modest effect sizes overall. 42

Concerning pharmacodynamic candidate genes involved in antipsychotic treatment response, the most consistent results have been obtained for genes of the dopaminergic and serotonergic systems. 40 , 42 Thus, an insertion deletion (Ins/Del) polymorphism of the dopamine D2 receptor gene (DRD2) was found significantly associated with antipsychotic drug response, Del allele carriers exhibiting a poorer response rate than patients with the Ins/Ins genotype. 55 Moreover, a Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) showed a consistent, though not significant trend for the Ser-allele and reduced clozapine response. 56 Also, two polymorphisms in the IITR2A gene (His452Tyr and T102C) were found associated with clozapine response. 57 Another receptor gene of the serotonergic system (HTR2C) contained a C759T polymorphism, the C-allele of which conferred a significantly increased risk for antipsychotic-induced weight gain, one of the most consistent associations observed in antipsychotics pharmacogenetics. 58 , 59 Strong candidates known to be involved in the genetics of obesity, the melanocortin 4 receptor (MC4R) and leptin genes, were also suggested to be prominent risk factors predisposing to this serious adverse effect of antipsychotics. 58 , 59 Finally, several polymorphisms of the HLA-system, specifically of HLA-B38, DR4 and DQw3 60 and HLA-DQB1 and HLA-B 61 were found associated with clozapine-induced agranulocytosis, another serious side effect of antipsychotics. For a detailed summary of the genetics of common antipsychotic-induced adverse effects see also MacNeil and Müller. 62 Numerous studies were performed with candidate genes potentially involved in lithium response, which all were inconclusive, in part also due to its unresolved underlying biology. 42

Translating pharmacogenomics to clinical practice

Pharmacogenomic studies aimed to improve individual psychiatric drug treatment through pre-emptive genotyping, which would allow adjustment of dosages to reduce the risk of overdosing and serious side effects, or a change of drug. In sum, the scientific evidence to support the clinical validity of pharmacogenetic testing is still insufficient for most gene-drug pairs. Moreover, the clinical utility of specific gene-drug pairs has not yet been clearly demonstrated in adequately powered, double-blind clinical trials, which need to be conducted to clarify whether patients benefit substantially from genotype-guided treatment compared to “treatment as usual.” Also other factors that influence treatment response such as co-medication, age, gender, disease symptoms/comorbidity, smoking and diet and, importantly, ethnic background, need to be taken into account and studied further. Despite these limitations, CYP2D6 and CYP2C19 testing has already been recommended for clinical use, 63 and guidelines for using and generating genetic information have been outlined. 64 First implementation studies using CYP2D6 and CYP2C19 genotype information in clinical practice indicated that pharmacogenetic testing was very well accepted by both physicians and patients, could particularly be beneficial for non-extensive metabolizing patients, and hold great potential for optimization of drug treatment in psychiatry. 45 , 65 Recently, the Individualized Medicine: Pharmacogenetics Assessment and Clinical Treatment (IMPACT) study was launched to demonstrate the feasibility- and utility of pharmacogenetic testing on a large scale and facilitate implementation of this testing in routine health care practice. 66

The implementation of pharmacogenomics in the clinic is supported by the establishment of comprehensive resources such as the Pharmacogenomic Knowledge Base (PharmGKB) (https://www.pharmgkb.org), and international expert groups that enable objective and transparent assessment of existing pharmacogenetic studies to derive clinical recommendations, such as the Clinical Pharmacogenomics Implementation Consortium (CPIC). Accordingly, CPIC performs a systematic review/evaluation of the comprehensive literature curated in PharmGKB to develop peer-reviewed gene-drug guidelines that are published and updated periodically (for further information on pharmacogenomics resources see Pouget et al 40 and Müller et al). 42 Thus, CPIC guidelines for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants as well as SSRIs 44 , 46 have been published. These guidelines provide concrete information for the interpretation of genetic tests, that is, a list of existing genotypes with their “likely (pharmacokinetic) phenotypes” assigned and corresponding dosing recommendations or alternative therapeutic recommendations (suggesting selection of a drug not primarily metabolized by CYP2D6). The expert groups' recommendations are further translated by national or cross-national regulatory agencies. Thus, the US Food and Drug Administration (FDA) and other agencies distinguish for instance four categories, “required,” “recommended,” “actionable,” and “informative,” this classification of gene-drug pairs often varying between agencies and countries.

In sum, there is very good consensus concerning the pharmacogenetic testing of CYP2D6, which is “recommended” for therapy with tricyclic antidepressants with particular reference to the increased risk for serious side effects in patients with PM-status. Also the testing of CYP2C19 is considered “particularly clinically relevant.” Beyond avoiding harm, testing both CYPs is considered to improve therapy through selection of alternative drugs and provide useful information for many other diseases. Agencies such as the FDA have begun to include pharmacogenomics information in drug labeling and recommend genetic testing for now 25 psychiatric drugs. 42 As emphasized in the Genetic Testing Statement released by the ISPG, clinicians are encouraged to consider such recommendations in their treatment decisions and to “stay current on changes to drug labeling and adverse event reports” (https://ispg. net/genetic-testing-statement/). The FDA and other agencies “require” genetic testing in patients of Asian ancestry before carbamazepine treatment; carriers of the major histocompatibility allele HLA-B*15:02 are at highly increased risk to develop Stevens-Johnson syndrome (SJS), a potentially lethal skin disease. The only other “required” genetic test concerns children and adult patients who receive pimozide, an antipsychotic, to prevent side effects in CYP2D6-PM.

Conclusions and outlook

Psychiatric genetics has generated very promising results in terms of risk variants associated with major psychiatric disorders and treatment outcome. Despite these successes, psychiatry still lags behind other fields in medicine in terms of translation of existing knowledge into diagnostic genetic tests that could facilitate early diagnosis and accurate classification of disorders. The nature of genotype-phenotype-relationships has remained largely elusive, and the “fundamental biology” of psychiatric disorders has yet to be revealed. 1 , 5 Significant progress can be expected from several lines of technological advancement/development. For example, there is reason to be excited about the prospect of WGS being increasingly implemented as the assay of choice for both gene discovery and diagnostic testing in highly heterogeneous disorders. Advantages of WGS include its comprehensiveness, with the analysis of coding and non-coding sequence, the improved coverage of sequences, and in fact, of whole genes that were previously not easily sequenced, as well as the detection of all types of genetic variation. This also promises to increase diagnostic yield. Moreover, it will allow establishment of a catalogue of non-coding variation, which is assumed to contribute substantially to the development of psychiatric disorders. One could envisage a comprehensive, genome -wide panel assay, where one assesses all known variants with proven associations to psychiatric disorders in an individual patient. Since these disorders, as well as individual drug response, are complex traits which can be influenced by multiple genes, further progress can be expected through assessment of gene-gene interactions, gene networks and the application of systems approaches. 67 Complex traits are also significantly influenced by environmental factors. Thus, the analysis of the epigenome as the interface between genome and environment is expected to contribute key insights into the development of psychiatric disorders. 68 , 69 True genome-wide assessments of epigenetic marks, such as DNA methylation, or chromatin modifications have become possible, mainly also through progress in second-generation DNA sequencing methods. 69 Furthermore, the inaccessibility of the human brain can now be overcome by stem cell approaches, which make it possible to study (pluripotent stem cell-derived) neurons from patients “in a dish.” 70 The generation of CNS organoids as model systems may open new avenues towards precision drug treatment. Beyond technological advancements, a reconsideration/rethinking of previous research concepts could critically move the field forward. As outlined by Kapur et al, 71 to achieve clinical utility of diagnostic genetic testing may require a new approach. Rather than comparing prototypic patients to healthy controls, the field should focus on “identifying biologically homogeneous subtypes that cut across phenotypic diagnosis.” Validating such biomarker/genetically-defined subtypes will require longitudinal studies of individual patients, providing the “natural basis for a 'stratified' psychiatry that will improve clinical outcomes across conventional diagnostic boundaries,” ultimately more compatible with the major goal of precision medicine 71 —and the findings obtained to date.

Selected abbreviations and acronyms

IMAGES

  1. Genetic disorders research and presentation task

    genetic disorders research papers

  2. Psychological Disorders Essay

    genetic disorders research papers

  3. Genetic Disorders

    genetic disorders research papers

  4. Genetic Disorder / Abnormality Paper Research Paper

    genetic disorders research papers

  5. PPT

    genetic disorders research papers

  6. (PDF) Genetic Algorithm

    genetic disorders research papers

COMMENTS

  1. Human Molecular Genetics and Genomics

    With the cost of sequencing a complete genome having dropped from $3 billion during the Human Genome Project to $600 today, there are growing efforts to create large-scale biobanks of complete...

  2. Disease genetics

    Disease genetics, of human, animal and plant diseases, investigates the consequences of pathogenic (host) genetic variants as the major causes of heritable disorders (monogenic diseases)...

  3. Rare Genetic Diseases: Nature's Experiments on Human Development

    The genetic tractability of monogenic defects, their penetrance in early life, and the expanding collection of human mutations and curated phenotypes make rare diseases ideal targets of study for discovering evolutionarily conserved biological mechanisms that go awry in common human diseases.

  4. The genetic basis of disease

    This review explores the genetic basis of human disease, including single gene disorders, chromosomal imbalances, epigenetics, cancer and complex disorders, and considers how our understanding and technological advances can be applied to provision of appropriate diagnosis, management and therapy for patients.

  5. Genetics of congenital heart disease: a narrative review of recent

    While there have been significant advances in the elucidation of the genetic etiologies for other forms of inherited cardiac disease such as cardiomyopathy and arrhythmias, it has only been with the increased understanding of the molecular pathways regulating cardiovascular development over the past couple of decades that the genetic basis of CH...

  6. Genetics research

    Genetics research is the scientific discipline concerned with the study of the role of genes in traits such as the development of disease. It has a key role in identifying potential targets for...

  7. Genomic data in the All of Us Research Program

    Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics 1,2,3,4.The All of Us Research Program is a ...

  8. Children with a rare congenital genetic disorder: a systematic review

    Published: 17 October 2022 Children with a rare congenital genetic disorder: a systematic review of parent experiences Charlotte von der Lippe, Ingrid Neteland & Kristin Billaud Feragen Orphanet Journal of Rare Diseases 17, Article number: 375 ( 2022 ) Cite this article 4537 Accesses 12 Citations 3 Altmetric Metrics Abstract Background

  9. Genetics articles: The New England Journal of Medicine

    Feb 1 Perspective Secondary Cancers after Chimeric Antigen Receptor T-Cell Therapy N. Verdun and P. Marks Original Article Feb 15, 2024 High-Dose ERT, Rituximab, and Early HSCT in an Infant with...

  10. The genetic basis of disease

    This review explores the genetic basis of human disease, including single gene disorders, chromosomal imbalances, epigenetics, cancer and complex disorders, and considers how our understanding and technological advances can be applied to provision of appropriate diagnosis, management and therapy for patients.

  11. Carrier Testing for Severe Childhood Recessive Diseases by Next ...

    Although diseases inherited in a Mendelian fashion are rare, together they account for about 20% of deaths in infancy. For Mendelian diseases that are recessive (of which there are more than 1000), screening before pregnancy (preconception screening) together with genetic counseling of those carrying a mutant allele could reduce the incidence of these diseases and the suffering that they incur.

  12. (PDF) Human genetic disorders

    Human genetic disorders October 2018 Authors: Hamza Abdullah AGCT RESEARCH Abstract Human is a one of the Almighty's complex creation. Humans are made up of trillions of cells and these cells...

  13. Evidence for 28 genetic disorders discovered by combining ...

    Evidence for 28 genetic disorders discovered by combining healthcare and research data | Nature Article Published: 14 October 2020 Evidence for 28 genetic disorders discovered by...

  14. 2022: a pivotal year for diagnosis and treatment of rare genetic diseases

    We can diagnose a critically ill child with a genetic disease by rapid whole-genome sequencing (WGS) in only 7 h ( Gorzynski et al. 2022 ). More than 500 childhood-onset genetic diseases have at least somewhat effective treatments ( Owen et al. 2022; http://gtrx.rbsapp.net ).

  15. (PDF) The genetic basis of disease

    This review explores the genetic basis of human disease, including single gene disorders, chromosomal imbalances, epigenetics, cancer and complex disorders, and considers how our...

  16. Key genes linked to DNA damage and human disease uncovered

    The findings help shed light on genetic factors influencing the health of human genomes over a lifespan and disease development. Professor Gabriel Balmus, senior author of the study at the UK ...

  17. Genetics of neurodegenerative diseases: an overview

    Genetics plays an essential role in translational research, ultimately aiming to develop novel disease-modifying therapies for neurodegenerative disorders. We anticipate that individual genetic profiling will also be increasingly relevant in a clinical context, with implications for patient care in line with the proposed ideal of personalized ...

  18. Genetic Disorders

    List of Genetic Disorders This list of genetic, orphan and rare diseases is provided for informational purposes only and is by no means comprehensive. About Achondroplasia About Alpha-1 Antitrypsin Deficiency About Antiphospholipid Syndrome About Attention Deficit Hyperactivity Disorder About Autism

  19. Researchers optimize genetic tests for diverse populations to tackle

    Improved genetic tests more accurately assess disease risk regardless of genetic ancestry. To prevent an emerging genomic technology from contributing to health disparities, a scientific team funded by the National Institutes of Health has devised new ways to improve a genetic testing method called a polygenic risk score. Since polygenic risk ...

  20. A brief history of human disease genetics

    A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 ...

  21. A Comprehensive Review on Various Aspects of Genetic Disorders

    A Comprehensive Review on Various Aspects of Genetic Disorders February 2015 Journal of Biology and Life Science DOI: CC BY 4.0 Authors: Asad Khan Hazara University Ihsan Khan University of...

  22. New insights from the last decade of research in psychiatric genetics

    Psychiatric genetics has made substantial progress in the last decade, providing new insights into the genetic etiology of psychiatric disorders, and paving the way for precision psychiatry, in which individual genetic profiles may be used to personalize risk assessment and inform clinical decision‐making.

  23. 275 Million New Genetic Variants Identified in NIH Precision Medicine

    Study details the unprecedented scale, diversity, and power of the All of Us Research Program. Leer en enspañol. Researchers have discovered more than 275 million previously unreported genetic variants, identified from data shared by nearly 250,000 participants of the National Institutes of Health's All of Us Research Program.Half of the genomic data are from participants of non-European ...

  24. Rare diseases, common challenges

    Published: 14 March 2022 Rare diseases, common challenges Nature Genetics 54 , 215 ( 2022) Cite this article 10k Accesses 7 Citations 9 Altmetric Metrics The genetics community has a...

  25. NIH study uncovers 275MILLION entirely new genetic variants that ...

    In one of the papers, of which nearly 40 percent of participants were from minority backgrounds, researchers found 611 genetic markers that could raise the risk of suffering from diabetes — 145 ...

  26. (PDF) Human Genetic Diseases

    Of course, this disease ISSN: 2252-8938 Int J Artif Intell, Vol. 12, No. 3, September 2023: 1019-1025 1020 needs to be confirmed by complex genetic testing, and genetic testing is only available ...

  27. Gene therapy: advances, challenges and perspectives

    Genetic-scientific studies initiated in the early 1850s, when the Austrian monk, Gregor Mendel, in a series of experiments with green peas, described the inheritance pattern by observing the traces that were inherited as separate units, which we know today as genes.

  28. Genetic tests could evaluate risk for 10 common illnesses

    By Dennis Thompson, HealthDay News. The tests evaluate a person's specific genetic risk for conditions like atrial fibrillation, breast cancer, kidney disease, heart disease, high cholesterol ...

  29. The role of genetics and genomics in clinical psychiatry

    From the mid-1980s, family, twin, and adoption studies have provided consistent evidence for aggregate genetic effects for psychiatric disorders, demonstrating the substantial role of genetic factors in the etiology of mental illness. 1 The heritability estimates for most psychiatric disorders were found to be high, between 0.4 and 0.8. 2 These ...