genetic disorders research papers

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• 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

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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.

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.

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

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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

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Rare genetic disorders in India: Current status, challenges, and CRISPR-based therapy

• Published: 19 February 2024
• Volume 49 , article number  28 , ( 2024 )

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• Pallabi Bhattacharyya 1   na1 ,
• Kanikah Mehndiratta 1 , 2   na1 ,
• Souvik Maiti 1 , 3 &
• Debojyoti Chakraborty   ORCID: orcid.org/0000-0003-1460-7594 1 , 3  

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Rare genetic diseases are a group of life-threatening disorders affecting significant populations worldwide and posing substantial challenges to healthcare systems globally. India, with its vast population, is also no exception. The country harbors millions of individuals affected by these fatal disorders, which often result from mutations in a single gene. The emergence of CRISPR-Cas9 technology, however, has ushered in a new era of hope in genetic therapies. CRISPR-based treatments hold the potential to precisely edit and correct disease-causing mutations, offering tailored solutions for rare genetic diseases in India. This review explores the landscape of rare genetic diseases in India along with national policies and major challenges, and examines the implications of CRISPR-based therapies for potential cure. It delves into the potential of this technology in providing personalized and effective treatments. However, alongside these promising prospects, some ethical considerations, regulatory challenges, and concerns about the accessibility of CRISPR therapies are also discussed since addressing these issues is crucial for harnessing the full power of CRISPR in tackling rare genetic diseases in India. By taking a multidisciplinary approach that combines scientific advancements, ethical principles, and regulatory frameworks, these complexities can be reconciled, paving the way for innovative and impactful healthcare solutions for rare diseases in India.

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Acknowledgements

This work was supported by an EMBO Investigator Award to DC and was carried out at CSIR-Institute of Genomics & Integrative Biology, India.

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Pallabi Bhattacharyya and Kanikah Mehndiratta contributed equally.

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Council of Scientific and Industrial Research, Institute of Genomics and Integrative Biology, New Delhi, India

Pallabi Bhattacharyya, Kanikah Mehndiratta, Souvik Maiti & Debojyoti Chakraborty

Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596, Frankfurt am Main, Germany

Kanikah Mehndiratta

Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

Souvik Maiti & Debojyoti Chakraborty

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PB and KM equally contributed to writing the manuscript. SM and DC critically supervised and finalized the manuscript.

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Correspondence to Debojyoti Chakraborty .

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Corresponding editor: A lok B hattacharya

This article is part of the Topical Collection: The Rare Genetic Disease Research Landscape in India.

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Bhattacharyya, P., Mehndiratta, K., Maiti, S. et al. Rare genetic disorders in India: Current status, challenges, and CRISPR-based therapy. J Biosci 49 , 28 (2024). https://doi.org/10.1007/s12038-023-00413-8

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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.

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Microbiome studies help explore treatments for genetic disorders

by University of Trento

A collaboration has led to the identification, in a bacterium of the intestine, of new CRISPR-Cas9 molecules that could have a clinical potential to treat genetic diseases such as retinitis pigmentosa, through sub-retinal injections. Anna Cereseto and Nicola Segata of the Department of Cellular, Computational and Integrative Biology of the University of Trento have joined forces and combined their expertise to develop new therapies for the treatment of genetic diseases.

A study, with Anna Cereseto and Nicola Segata as corresponding and senior authors, has been published in Nature Communications .

Researchers all over the world are investigating genomic therapies to find new treatments for genetic disorders. Genome editing using the CRISPR-Cas9 system is based on the use of the Cas9 protein, which works like a pair of molecular scissors that can be programmed to make specific modifications in the genome to cut or replace harmful DNA sequences, correcting the mutations that cause diseases.

This biotechnology was discovered in 2012 in the United States and has already led to one approved therapy, a drug for sickle cell disease.

Now the study conducted by the University of Trento brings genomic research one step forward.

"Compared with other CRISPR-Cas9 approaches, the one we have identified is precise and effective, and more compact. This new CRISPR-Cas9 molecule, as demonstrated by our experiments in the retina, will be more easily delivered to the organs that must be treated in therapies for genetic diseases," says Anna Cereseto, who has been involved in studies on the genomic editor since 2018 with the development of evoCas9.

Expanding the range of CRISPR-Cas tools is necessary to speed up the development of therapies for genetic diseases. This can be made by modifying natural enzymes, as was the case with evoCas9, but discovering already evolved enzymes that can work offers great advantages.

The collaboration with the laboratory of Computational Metagenomics of Nicola Segata has allowed the laboratory of Molecular Virology of Anna Cereseto to shed light on a vast natural reserve of CRISPR-Cas9 systems from which to draw new valuable tools for human genome editing.

"By interrogating a microbiome genome database that we have created over several years, we discovered a large number of Cas9 with interesting properties for genome editing," say Anna Cereseto and Nicola Segata.

"We have discovered a great variety of CRISPR-Cas9 in the bacteria that inhabit the intestine. In particular, we have identified the CoCas9 nuclease, a very active group of enzymes with a small molecular size, about a thousand amino acids, in Collinsella, a bacterial genus that is often found in human guts."

"The sequencing of the entire microbiome using a metagenomic approach, followed by the laboratory reconstruction of the assembled genomes, has led to the identification of a huge variety of species. The discovery of a collection of new Cas9 nucleases, including CoCas9, makes the genome editing toolkit even larger," they point out.

They conclude, "The difficulty of administration still hampers the development of therapies for genetic diseases . However, CoCas9, thanks to its small size, shows potential for gene therapy applications and is therefore a potential candidate for optimization through engineering approaches, which deserves further investigation. We are already working on clinical development projects."

Journal information: Nature Communications

Provided by University of Trento

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Study Suggests Genetics as a Cause, Not Just a Risk, for Some Alzheimer’s

People with two copies of the gene variant APOE4 are almost certain to get Alzheimer’s, say researchers, who proposed a framework under which such patients could be diagnosed years before symptoms.

By Pam Belluck

Scientists are proposing a new way of understanding the genetics of Alzheimer’s that would mean that up to a fifth of patients would be considered to have a genetically caused form of the disease.

Currently, the vast majority of Alzheimer’s cases do not have a clearly identified cause. The new designation, proposed in a study published Monday, could broaden the scope of efforts to develop treatments, including gene therapy, and affect the design of clinical trials.

It could also mean that hundreds of thousands of people in the United States alone could, if they chose, receive a diagnosis of Alzheimer’s before developing any symptoms of cognitive decline, although there currently are no treatments for people at that stage.

The new classification would make this type of Alzheimer’s one of the most common genetic disorders in the world, medical experts said.

“This reconceptualization that we’re proposing affects not a small minority of people,” said Dr. Juan Fortea, an author of the study and the director of the Sant Pau Memory Unit in Barcelona, Spain. “Sometimes we say that we don’t know the cause of Alzheimer’s disease,” but, he said, this would mean that about 15 to 20 percent of cases “can be tracked back to a cause, and the cause is in the genes.”

The idea involves a gene variant called APOE4. Scientists have long known that inheriting one copy of the variant increases the risk of developing Alzheimer’s, and that people with two copies, inherited from each parent, have vastly increased risk.

The new study , published in the journal Nature Medicine, analyzed data from over 500 people with two copies of APOE4, a significantly larger pool than in previous studies. The researchers found that almost all of those patients developed the biological pathology of Alzheimer’s, and the authors say that two copies of APOE4 should now be considered a cause of Alzheimer’s — not simply a risk factor.

The patients also developed Alzheimer’s pathology relatively young, the study found. By age 55, over 95 percent had biological markers associated with the disease. By 65, almost all had abnormal levels of a protein called amyloid that forms plaques in the brain, a hallmark of Alzheimer’s. And many started developing symptoms of cognitive decline at age 65, younger than most people without the APOE4 variant.

“The critical thing is that these individuals are often symptomatic 10 years earlier than other forms of Alzheimer’s disease,” said Dr. Reisa Sperling, a neurologist at Mass General Brigham in Boston and an author of the study.

She added, “By the time they are picked up and clinically diagnosed, because they’re often younger, they have more pathology.”

People with two copies, known as APOE4 homozygotes, make up 2 to 3 percent of the general population, but are an estimated 15 to 20 percent of people with Alzheimer’s dementia, experts said. People with one copy make up about 15 to 25 percent of the general population, and about 50 percent of Alzheimer’s dementia patients.

The most common variant is called APOE3, which seems to have a neutral effect on Alzheimer’s risk. About 75 percent of the general population has one copy of APOE3, and more than half of the general population has two copies.

Alzheimer’s experts not involved in the study said classifying the two-copy condition as genetically determined Alzheimer’s could have significant implications, including encouraging drug development beyond the field’s recent major focus on treatments that target and reduce amyloid.

Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York, who was not involved in the study, said that patients with two copies of APOE4 faced much higher safety risks from anti-amyloid drugs.

When the Food and Drug Administration approved the anti-amyloid drug Leqembi last year, it required a black-box warning on the label saying that the medication can cause “serious and life-threatening events” such as swelling and bleeding in the brain, especially for people with two copies of APOE4. Some treatment centers decided not to offer Leqembi, an intravenous infusion, to such patients.

Dr. Gandy and other experts said that classifying these patients as having a distinct genetic form of Alzheimer’s would galvanize interest in developing drugs that are safe and effective for them and add urgency to current efforts to prevent cognitive decline in people who do not yet have symptoms.

“Rather than say we have nothing for you, let’s look for a trial,” Dr. Gandy said, adding that such patients should be included in trials at younger ages, given how early their pathology starts.

Besides trying to develop drugs, some researchers are exploring gene editing to transform APOE4 into a variant called APOE2, which appears to protect against Alzheimer’s. Another gene-therapy approach being studied involves injecting APOE2 into patients’ brains.

The new study had some limitations, including a lack of diversity that might make the findings less generalizable. Most patients in the study had European ancestry. While two copies of APOE4 also greatly increase Alzheimer’s risk in other ethnicities, the risk levels differ, said Dr. Michael Greicius, a neurologist at Stanford University School of Medicine who was not involved in the research.

“One important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies substantially across different genetic ancestries,” said Dr. Greicius, who cowrote a study that found that white people with two copies of APOE4 had 13 times the risk of white people with two copies of APOE3, while Black people with two copies of APOE4 had 6.5 times the risk of Black people with two copies of APOE3.

“This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease,” he said, “and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

Under the current genetic understanding of Alzheimer’s, less than 2 percent of cases are considered genetically caused. Some of those patients inherited a mutation in one of three genes and can develop symptoms as early as their 30s or 40s. Others are people with Down syndrome, who have three copies of a chromosome containing a protein that often leads to what is called Down syndrome-associated Alzheimer’s disease .

Dr. Sperling said the genetic alterations in those cases are believed to fuel buildup of amyloid, while APOE4 is believed to interfere with clearing amyloid buildup.

Under the researchers’ proposal, having one copy of APOE4 would continue to be considered a risk factor, not enough to cause Alzheimer’s, Dr. Fortea said. It is unusual for diseases to follow that genetic pattern, called “semidominance,” with two copies of a variant causing the disease, but one copy only increasing risk, experts said.

The new recommendation will prompt questions about whether people should get tested to determine if they have the APOE4 variant.

Dr. Greicius said that until there were treatments for people with two copies of APOE4 or trials of therapies to prevent them from developing dementia, “My recommendation is if you don’t have symptoms, you should definitely not figure out your APOE status.”

He added, “It will only cause grief at this point.”

Finding ways to help these patients cannot come soon enough, Dr. Sperling said, adding, “These individuals are desperate, they’ve seen it in both of their parents often and really need therapies.”

Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck

The Fight Against Alzheimer’s Disease

Alzheimer’s is the most common form of dementia, but much remains unknown about this daunting disease..

How is Alzheimer’s diagnosed? What causes Alzheimer’s? We answered some common questions .

A study suggests that genetics can be a cause of Alzheimer’s , not just a risk, raising the prospect of diagnosis years before symptoms appear.

Determining whether someone has Alzheimer’s usually requires an extended diagnostic process . But new criteria could lead to a diagnosis on the basis of a simple blood test .

The F.D.A. has given full approval to the Alzheimer’s drug Leqembi. Here is what to know about i t.

Alzheimer’s can make communicating difficult. We asked experts for tips on how to talk to someone with the disease .

Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.

Volume 30, Number 7—July 2024

Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Domestic Dairy Cattle and Cats, United States, 2024

Suggested citation for this article

We report highly pathogenic avian influenza A(H5N1) virus in dairy cattle and cats in Kansas and Texas, United States, which reflects the continued spread of clade 2.3.4.4b viruses that entered the country in late 2021. Infected cattle experienced nonspecific illness, reduced feed intake and rumination, and an abrupt drop in milk production, but fatal systemic influenza infection developed in domestic cats fed raw (unpasteurized) colostrum and milk from affected cows. Cow-to-cow transmission appears to have occurred because infections were observed in cattle on Michigan, Idaho, and Ohio farms where avian influenza virus–infected cows were transported. Although the US Food and Drug Administration has indicated the commercial milk supply remains safe, the detection of influenza virus in unpasteurized bovine milk is a concern because of potential cross-species transmission. Continued surveillance of highly pathogenic avian influenza viruses in domestic production animals is needed to prevent cross-species and mammal-to-mammal transmission.

Highly pathogenic avian influenza (HPAI) viruses pose a threat to wild birds and poultry globally, and HPAI H5N1 viruses are of even greater concern because of their frequent spillover into mammals. In late 2021, the Eurasian strain of H5N1 (clade 2.3.4.4b) was detected in North America ( 1 , 2 ) and initiated an outbreak that continued into 2024. Spillover detections and deaths from this clade have been reported in both terrestrial and marine mammals in the United States ( 3 , 4 ). The detection of HPAI H5N1 clade 2.3.4.4b virus in severe cases of human disease in Ecuador ( 5 ) and Chile ( 6 ) raises further concerns regarding the pandemic potential of specific HPAI viruses.

In February 2024, veterinarians were alerted to a syndrome occurring in lactating dairy cattle in the panhandle region of northern Texas. Nonspecific illness accompanied by reduced feed intake and rumination and an abrupt drop in milk production developed in affected animals. The milk from most affected cows had a thickened, creamy yellow appearance similar to colostrum. On affected farms, incidence appeared to peak 4–6 days after the first animals were affected and then tapered off within 10–14 days; afterward, most animals were slowly returned to regular milking. Clinical signs were commonly reported in multiparous cows during middle to late lactation; ≈10%–15% illness and minimal death of cattle were observed on affected farms. Initial submissions of blood, urine, feces, milk, and nasal swab samples and postmortem tissues to regional diagnostic laboratories did not reveal a consistent, specific cause for reduced milk production. Milk cultures were often negative, and serum chemistry testing showed mildly increased aspartate aminotransferase, gamma-glutamyl transferase, creatinine kinase, and bilirubin values, whereas complete blood counts showed variable anemia and leukocytopenia.

In early March 2024, similar clinical cases were reported in dairy cattle in southwestern Kansas and northeastern New Mexico; deaths of wild birds and domestic cats were also observed within affected sites in the Texas panhandle. In > 1 dairy farms in Texas, deaths occurred in domestic cats fed raw colostrum and milk from sick cows that were in the hospital parlor. Antemortem clinical signs in affected cats were depressed mental state, stiff body movements, ataxia, blindness, circling, and copious oculonasal discharge. Neurologic exams of affected cats revealed the absence of menace reflexes and pupillary light responses with a weak blink response.

On March 21, 2024, milk, serum, and fresh and fixed tissue samples from cattle located in affected dairies in Texas and 2 deceased cats from an affected Texas dairy farm were received at the Iowa State University Veterinary Diagnostic Laboratory (ISUVDL; Ames, IA, USA). The next day, similar sets of samples were received from cattle located in affected dairies in Kansas. Milk and tissue samples from cattle and tissue samples from the cats tested positive for influenza A virus (IAV) by screening PCR, which was confirmed and characterized as HPAI H5N1 virus by the US Department of Agriculture National Veterinary Services Laboratory. Detection led to an initial press release by the US Department of Agriculture Animal and Plant Health Inspection Service on March 25, 2024, confirming HPAI virus in dairy cattle ( 7 ). We report the characterizations performed at the ISUVDL for HPAI H5N1 viruses infecting cattle and cats in Kansas and Texas.

Materials and Methods

Milk samples (cases 2–5) and fresh and formalin-fixed tissues (cases 1, 3–5) from dairy cattle were received at the ISUVDL from Texas on March 21 and from Kansas on March 22, 2024. The cattle exhibited nonspecific illness and reduced lactation, as described previously. The tissue samples for diagnostic testing came from 3 cows that were euthanized and 3 that died naturally; all postmortem examinations were performed on the premises of affected farms.

The bodies of 2 adult domestic shorthaired cats from a north Texas dairy farm were received at the ISUVDL for a complete postmortem examination on March 21, 2024. The cats were found dead with no apparent signs of injury and were from a resident population of ≈24 domestic cats that had been fed milk from sick cows. Clinical disease in cows on that farm was first noted on March 16; the cats became sick on March 17, and several cats died in a cluster during March 19–20. In total, >50% of the cats at that dairy became ill and died. We collected cerebrum, cerebellum, eye, lung, heart, spleen, liver, lymph node, and kidney tissue samples from the cats and placed them in 10% neutral-buffered formalin for histopathology.

At ISUVDL, we trimmed, embedded in paraffin, and processed formalin-fixed tissues from affected cattle and cats for hematoxylin/eosin staining and histologic evaluation. For immunohistochemistry (IHC), we prepared 4-µm–thick sections from paraffin-embedded tissues, placed them on Superfrost Plus slides (VWR, https://www.vwr.com ), and dried them for 20 minutes at 60°C. We used a Ventana Discovery Ultra IHC/ISH research platform (Roche, https://www.roche.com ) for deparaffinization until and including counterstaining. We obtained all products except the primary antibody from Roche. Automated deparaffination was followed by enzymatic digestion with protease 1 for 8 minutes at 37°C and endogenous peroxidase blocking. We obtained the primary influenza A virus antibody from the hybridoma cell line H16-L10–4R5 (ATCC, https://www.atcc.org ) and diluted at 1:100 in Discovery PSS diluent; we incubated sections with antibody for 32 minutes at room temperature. Next, we incubated the sections with a hapten-labeled conjugate, Discovery anti-mouse HQ, for 16 minutes at 37°C followed by a 16-minute incubation with the horse radish peroxidase conjugate, Discovery anti-HQ HRP. We used a ChromoMap DAB kit for antigen visualization, followed by counterstaining with hematoxylin and then bluing. Positive controls were sections of IAV-positive swine lung. Negative controls were sections of brain, lung, and eyes from cats not infected with IAV.

We diluted milk samples 1:3 vol/vol in phosphate buffered saline, pH 7.4 (Gibco/Thermo Fisher Scientific, https://www.thermofisher.com ) by mixing 1 unit volume of milk and 3 unit volumes of phosphate buffered saline. We prepared 10% homogenates of mammary glands, brains, lungs, spleens, and lymph nodes in Earle’s balanced salt solution (Sigma-Aldrich, https://www.sigmaaldrich.com ). Processing was not necessary for ocular fluid, rumen content, or serum samples. After processing, we extracted samples according to a National Animal Health Laboratory Network (NAHLN) protocol that had 2 NAHLN-approved deviations for ISUVDL consisting of the MagMax Viral RNA Isolation Kit for 100 µL sample volumes and a Kingfisher Flex instrument (both Thermo Fisher Scientific).

We performed real-time reverse transcription PCR (rRT-PCR) by using an NAHLN-approved assay with 1 deviation, which was the VetMAX-Gold SIV Detection kit (Thermo Fisher Scientific), to screen for the presence of IAV RNA. We tested samples along with the VetMAX XENO Internal Positive Control to monitor the possible presence of PCR inhibitors. Each rRT-PCR 96-well plate had 2 positive amplification controls, 2 negative amplification controls, 1 positive extraction control, and 1 negative extraction control. We ran the rRT-PCR on an ABI 7500 Fast thermocycler and analyzed data with Design and Analysis Software 2.7.0 (both Thermo Fisher Scientific). We considered samples with cycle threshold (Ct) values <40.0 to be positive for virus.

After the screening rRT-PCR, we analyzed IAV RNA–positive samples for the H5 subtype and H5 clade 2.3.4.4b by using the same RNA extraction and NAHLN-approved rRT-PCR protocols as described previously, according to standard operating procedures. We performed PCR on the ABI 7500 Fast thermocycler by using appropriate controls to detect H5-specific IAV. We considered samples with Ct values <40.0 to be positive for the IAV H5 subtype.

We conducted genomic sequencing of 2 milk samples from infected dairy cattle from Texas and 2 tissue samples (lung and brain) from cats that died at a different Texas dairy. We subjected the whole-genome sequencing data to bioinformatics analysis to assemble the 8 different IAV segment sequences according to previously described methods ( 8 ). We used the hemagglutinin (HA) and neuraminidase (NA) sequences for phylogenetic analysis. We obtained reference sequences for the HA and NA segments of IAV H5 clade 2.3.4.4 from publicly available databases, including GISAID ( https://www.gisaid.org ) and GenBank. We aligned the sequences by using MAFFT version 7.520 software ( https://mafft.cbrc.jp/alignment/server/index.html ) to create multiple sequence alignments for subsequent phylogenetic analysis. We used IQTree2 ( https://github.com/iqtree/iqtree2 ) to construct the phylogenetic tree from the aligned sequences. The software was configured to automatically identify the optimal substitution model by using the ModelFinder Plus option, ensuring the selection of the most suitable model for the dataset and, thereby, improving the accuracy of the reconstructed tree. We visualized the resulting phylogenetic tree by using iTOL ( https://itol.embl.de ), a web-based platform for interactive tree exploration and annotation.

Gross Lesions in Cows and Cats

All cows were in good body condition with adequate rumen fill and no external indications of disease. Postmortem examinations of the affected dairy cows revealed firm mammary glands typical of mastitis; however, mammary gland lesions were not consistent. Two cows that were acutely ill before postmortem examination had grossly normal milk and no abnormal mammary gland lesions. The gastrointestinal tract of some cows had small abomasal ulcers and shallow linear erosions of the intestines, but those observations were also not consistent in all animals. The colon contents were brown and sticky, suggesting moderate dehydration. The feces contained feed particles that appeared to have undergone minimal ruminal fermentation. The rumen contents had normal color and appearance but appeared to have undergone minimal fermentation.

The 2 adult cats (1 intact male, 1 intact female) received at the ISUVDL were in adequate body and postmortem condition. External examination was unremarkable. Mild hemorrhages were observed in the subcutaneous tissues over the dorsal skull, and multifocal meningeal hemorrhages were observed in the cerebrums of both cats. The gastrointestinal tracts were empty, and no other gross lesions were observed.

Microscopic Lesions in Cows and Cats

Figure 1 . Mammary gland lesions in cattle in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. A, B) Mammary gland...

The chief microscopic lesion observed in affected cows was moderate acute multifocal neutrophilic mastitis ( Figure 1 ); however, mammary glands were not received from every cow. Three cows had mild neutrophilic or lymphocytic hepatitis. Because they were adult cattle, other observed microscopic lesions (e.g., mild lymphoplasmacytic interstitial nephritis and mild to moderate lymphocytic abomasitis) were presumed to be nonspecific, age-related changes. We did not observe major lesions in the other evaluated tissues. We performed IHC for IAV antigen on all evaluated tissues; the only tissues with positive immunoreactivity were mastitic mammary glands from 2 cows that showed nuclear and cytoplasmic labeling of alveolar epithelial cells and cells within lumina ( Figure 1 ) and multifocal germinal centers within a lymph node from 1 cow ( Table 1 ).

Figure 2 . Lesions in cat tissues in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. Tissue sections were stained with...

Both cats had microscopic lesions consistent with severe systemic virus infection, including severe subacute multifocal necrotizing and lymphocytic meningoencephalitis with vasculitis and neuronal necrosis, moderate subacute multifocal necrotizing and lymphocytic interstitial pneumonia, moderate to severe subacute multifocal necrotizing and lymphohistiocytic myocarditis, and moderate subacute multifocal lymphoplasmacytic chorioretinitis with ganglion cell necrosis and attenuation of the internal plexiform and nuclear layers ( Table 2 ; Figure 2 ). We performed IHC for IAV antigen on multiple tissues (brain, eye, lung, heart, spleen, liver, and kidney). We detected positive IAV immunoreactivity in brain (intracytoplasmic, intranuclear, and axonal immunolabeling of neurons), lung, and heart, and multifocal and segmental immunoreactivity within all layers of the retina ( Figure 2 ).

PCR Data from Cows and Cats

We tested various samples from 8 clinically affected mature dairy cows by IAV screening and H5 subtype-specific PCR ( Table 3 ). Milk and mammary gland homogenates consistently showed low Ct values: 12.3–16.9 by IAV screening PCR, 17.6–23.1 by H5 subtype PCR, and 14.7–20.0 by H5 2.3.4.4 clade PCR (case 1, cow 1; case 2, cows 1 and 2; case 3, cow 1; and case 4, cow 1). We forwarded the samples to the National Veterinary Services Laboratory, which confirmed the virus was an HPAI H5N1 virus strain.

When available, we also tested tissue homogenates (e.g., lung, spleen, and lymph nodes), ocular fluid, and rumen contents from 6 cows by IAV and H5 subtype-specific PCR ( Table 3 ). However, the PCR findings were not consistent. For example, the tissue homogenates and ocular fluid tested positive in some but not all cows. In case 5, cow 1, the milk sample tested negative by IAV screening PCR, but the spleen homogenate tested positive by IAV screening, H5 subtype, and H5 2.3.4.4 PCR. For 2 cows (case 3, cow 1; and case 4, cow 1) that had both milk and rumen contents available, both samples tested positive for IAV. Nevertheless, all IAV-positive nonmammary gland tissue homogenates, ocular fluid, and rumen contents had markedly elevated Ct values in contrast to the low Ct values for milk and mammary gland homogenate samples.

We tested brain and lung samples from the 2 cats (case 6, cats 1 and 2) by IAV screening and H5 subtype-specific PCR ( Table 3 ). Both sample types were positive by IAV screening PCR; Ct values were 9.9–13.5 for brain and 17.4–24.4 for lung samples, indicating high amounts of virus nucleic acid in those samples. The H5 subtype and H5 2.3.4.4 PCR results were also positive for the brain and lung samples; Ct values were consistent with the IAV screening PCR ( Table 3 ).

Phylogenetic Analyses

We assembled the sequences of all 8 segments of the HPAI viruses from both cow milk and cat tissue samples. We used the hemagglutinin (HA) and neuraminidase (NA) sequences specifically for phylogenetic analysis to delineate the clade of the HA gene and subtype of the NA gene.

Figure 3 . Phylogenetic analysis of hemagglutinin gene sequences in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. Colors indicate different...

For HA gene analysis, both HA sequences derived from cow milk samples exhibited a high degree of similarity, sharing 99.88% nucleotide identity, whereas the 2 HA sequences from cat tissue samples showed complete identity at 100%. The HA sequences from the milk samples had 99.94% nucleotide identities with HA sequences from the cat tissues, resulting in a distinct subcluster comprising all 4 HA sequences, which clustered together with other H5N1 viruses belonging to clade 2.3.4.4b ( Figure 3 ). The HA sequences were deposited in GenBank (accession nos. PP599465 [case 2, cow 1], PP599473 [case 2, cow 2], PP692142 [case 6, cat 1], and PP692195 [case 6, cat 2]).

Figure 4 . Phylogenetic analysis of neuraminidase gene sequences in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. Colors indicate different...

For NA gene analysis, the 2 NA sequences obtained from cow milk samples showed 99.93% nucleotide identity. Moreover, the NA sequences derived from the milk samples exhibited complete nucleotide identities (100%) with those from the cat tissues. The 4 NA sequences were grouped within the N1 subtype of HPAI viruses ( Figure 4 ). The NA sequences were deposited in GenBank (accession nos. PP599467 [case 2, cow 1], PP599475 [case 2, cow 2], PP692144 [case 6, cat 1], and PP692197 [case 6, cat 2]).

This case series differs from most previous reports of IAV infection in bovids, which indicated cattle were inapparently infected or resistant to infection ( 9 ). We describe an H5N1 strain of IAV in dairy cattle that resulted in apparent systemic illness, reduced milk production, and abundant virus shedding in milk. The magnitude of this finding is further emphasized by the high death rate (≈50%) of cats on farm premises that were fed raw colostrum and milk from affected cows; clinical disease and lesions developed that were consistent with previous reports of H5N1 infection in cats presumably derived from consuming infected wild birds ( 10 – 12 ). Although exposure to and consumption of dead wild birds cannot be completely ruled out for the cats described in this report, the known consumption of unpasteurized milk and colostrum from infected cows and the high amount of virus nucleic acid within the milk make milk and colostrum consumption a likely route of exposure. Therefore, our findings suggest cross-species mammal-to-mammal transmission of HPAI H5N1 virus and raise new concerns regarding the potential for virus spread within mammal populations. Horizontal transmission of HPAI H5N1 virus has been previously demonstrated in experimentally infected cats ( 13 ) and ferrets ( 14 ) and is suspected to account for large dieoffs observed during natural outbreaks in mink ( 15 ) and sea lions ( 16 ). Future experimental studies of HPAI H5N1 virus in dairy cattle should seek to confirm cross-species transmission to cats and potentially other mammals.

Clinical IAV infection in cattle has been infrequently reported in the published literature. The first report occurred in Japan in 1949, where a short course of disease with pyrexia, anorexia, nasal discharge, pneumonia, and decreased lactation developed in cattle ( 17 ). In 1997, a similar condition occurred in dairy cows in southwest England leading to a sporadic drop in milk production ( 18 ), and IAV seroconversion was later associated with reduced milk yield and respiratory disease ( 19 – 21 ). Rising antibody titers against human-origin influenza A viruses (H1N1 and H3N2) were later again reported in dairy cattle in England, which led to an acute fall in milk production during October 2005–March 2006 ( 22 ). Limited reports of IAV isolation from cattle exist; most reports occurred during the 1960s and 1970s in Hungary and in the former Soviet Union, where H3N2 was recovered from cattle experiencing respiratory disease ( 9 , 23 ). Direct detection of IAV in milk and the potential transmission from cattle to cats through feeding of unpasteurized milk has not been previously reported.

An IAV-associated drop in milk production in dairy cattle appears to have occurred during > 4 distinct periods and within 3 widely separated geographic areas: 1949 in Japan ( 17 ), 1997–1998 and 2005–2006 in Europe ( 19 , 21 ), and 2024 in the United States (this report). The sporadic occurrence of clinical disease in dairy cattle worldwide might be the result of changes in subclinical infection rates and the presence or absence of sufficient baseline IAV antibodies in cattle to prevent infection. Milk IgG, lactoferrin, and conglutinin have also been suggested as host factors that might reduce susceptibility of bovids to IAV infection ( 9 ). Contemporary estimates of the seroprevalence of IAV antibodies in US cattle are not well described in the published literature. One retrospective serologic survey in the United States in the late 1990s showed 27% of serum samples had positive antibody titers and 31% had low-positive titers for IAV H1 subtype-specific antigen in cattle with no evidence of clinical infections ( 24 ). Antibody titers for H5 subtype-specific antigen have not been reported in US cattle.

The susceptibility of domestic cats to HPAI H5N1 is well-documented globally ( 10 – 12 , 25 – 28 ), and infection often results in neurologic signs in affected felids and other terrestrial mammals ( 4 ). Most cases in cats result from consuming infected wild birds or contaminated poultry products ( 12 , 27 ). The incubation period in cats is short; clinical disease is often observed 2–3 days after infection ( 28 ). Brain tissue has been suggested as the best diagnostic sample to confirm HPAI virus infection in cats ( 10 ), and our results support that finding. One unique finding in the cats from this report is the presence of blindness and microscopic lesions of chorioretinitis. Those results suggest that further investigation into potential ocular manifestations of HPAI H5N1 virus infection in cats might be warranted.

The genomic sequencing and subsequent analysis of clinical samples from both bovine and feline sources provided considerable insights. The HA and NA sequences derived from both bovine milk and cat tissue samples from different Texas farms had a notable degree of similarity. Those findings strongly suggest a shared origin for the viruses detected in the dairy cattle and cat tissues. Further research, case series investigations, and surveillance data are needed to better understand and inform measures to curtail the clinical effects, shedding, and spread of HPAI viruses among mammals. Although pasteurization of commercial milk mitigates risks for transmission to humans, a 2019 US consumer study showed that 4.4% of adults consumed raw milk > 1 time during the previous year ( 29 ), indicating a need for public awareness of the potential presence of HPAI H5N1 viruses in raw milk.

Ingestion of feed contaminated with feces from wild birds infected with HPAI virus is presumed to be the most likely initial source of infection in the dairy farms. Although the exact source of the virus is unknown, migratory birds (Anseriformes and Charadriiformes) are likely sources because the Texas panhandle region lies in the Central Flyway, and those birds are the main natural reservoir for avian influenza viruses ( 30 ). HPAI H5N1 viruses are well adapted to domestic ducks and geese, and ducks appear to be a major reservoir ( 31 ); however, terns have also emerged as an important source of virus spread ( 32 ). The mode of transmission among infected cattle is also unknown; however, horizontal transmission has been suggested because disease developed in resident cattle herds in Michigan, Idaho, and Ohio farms that received infected cattle from the affected regions, and those cattle tested positive for HPAI H5N1 ( 33 ). Experimental studies are needed to decipher the transmission routes and pathogenesis (e.g., replication sites and movement) of the virus within infected cattle.

In conclusion, we showed that dairy cattle are susceptible to infection with HPAI H5N1 virus and can shed virus in milk and, therefore, might potentially transmit infection to other mammals via unpasteurized milk. A reduction in milk production and vague systemic illness were the most commonly reported clinical signs in affected cows, but neurologic signs and death rapidly developed in affected domestic cats. HPAI virus infection should be considered in dairy cattle when an unexpected and unexplained abrupt drop in feed intake and milk production occurs and for cats when rapid onset of neurologic signs and blindness develop. The recurring nature of global HPAI H5N1 virus outbreaks and detection of spillover events in a broad host range is concerning and suggests increasing virus adaptation in mammals. Surveillance of HPAI viruses in domestic production animals, including cattle, is needed to elucidate influenza virus evolution and ecology and prevent cross-species transmission.

Dr. Burrough is a professor and diagnostic pathologist at the Iowa State University College of Veterinary Medicine and Veterinary Diagnostic Laboratory. His research focuses on infectious diseases of livestock with an emphasis on swine.

Acknowledgment

We thank the faculty and staff at the ISUVDL who contributed to the processing and analysis of clinical samples in this investigation, the veterinarians involved with clinical assessments at affected dairies and various conference calls in the days before diagnostic submissions that ultimately led to the detection of HPAI virus in the cattle, and the US Department of Agriculture National Veterinary Services Laboratory and NAHLN for their roles and assistance in providing their expertise, confirmatory diagnostic support, and communications surrounding the HPAI virus cases impacting lactating dairy cattle.

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• Figure 1 . Mammary gland lesions in cattle in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. A, B) Mammary...
• Figure 2 . Lesions in cat tissues in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. Tissue sections were stained...
• Figure 3 . Phylogenetic analysis of hemagglutinin gene sequences in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. Colors indicate...
• Figure 4 . Phylogenetic analysis of neuraminidase gene sequences in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. Colors indicate...
• Table 1 . Microscopic lesions observed in cattle in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024
• Table 2 . Microscopic lesions observed in cats in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024
• Table 3 . PCR results from various specimens in study of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024

Suggested citation for this article : Burrough ER, Magstadt DR, Petersen B, Timmermans SJ, Gauger PC, Zhang J, et al. Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus infection in domestic dairy cattle and cats, United States, 2024. Emerg Infect Dis. 2024 Jul [ date cited ]. https://doi.org/10.3201/eid3007.240508

DOI: 10.3201/eid3007.240508

Original Publication Date: April 29, 2024

Table of Contents – Volume 30, Number 7—July 2024

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• Brief Communication
• Published: 04 May 2023

Global trends and themes in genetic counseling research

• Wan Nur Amalina Zakaria   ORCID: orcid.org/0000-0001-5709-1861 1 ,
• Sook-Yee Yoon 2 ,
• Adi Wijaya   ORCID: orcid.org/0000-0001-5339-0231 3 ,
• Asma Hayati Ahmad   ORCID: orcid.org/0000-0001-5447-0356 4 ,
• Rahimah Zakaria 4 &
• Zahiruddin Othman 5  

European Journal of Human Genetics volume  31 ,  pages 1181–1184 ( 2023 ) Cite this article

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• Health care
• Health services

This article seeks to highlight the most recent trends and themes in genetic counseling that are of broad interest. A total of 3505 documents were published between 1952 and 2021, with a trend toward increase in paper/year. The most common documents are original articles (2515, 71.8%), followed by review articles (341, 9.7%). Journal of Genetic Counseling publishes the highest number of genetic counseling articles (587, 16.7%), followed by Clinical Genetics (103, 2.9%) and the South American Journal of Medical Genetics (95, 2.7%). Co-occurrence analysis revealed five research themes: genetic testing, cancer, genetic counselor, prenatal diagnosis, and psychiatry. The genetic counselor theme contained most of the recent keywords, including “covid-19,” “underrepresented population,” “service delivery models,” “workforce,” “disparities,” “service delivery,” “professional development,” “cultural competence,” “access,” “diversity,” “telemedicine,” and “health literacy.” Genetic counseling researchers may use these keywords to find topics pertinent to their future research and practice.

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Introduction.

The term “genetic counseling” was first coined by an American scientist, Sheldon C. Reed, in 1947 [ 1 ]. According to the Ad Hoc Committee of the American Society of Human Genetics, genetic counseling addresses human issues related to the incidence or risk of a genetic disorder in a family [ 2 ]. Seymour Kessler later defined genetic counseling as psychological contact or psychotherapy [ 3 ]. The 2006 National Society of Genetic Counselors task force described genetic counseling as helping people understand and adapt to the physical, psychological, and familial implications of genetic contributions to disease [ 4 ].

Future trends in clinical genetic and genetic services are fast evolving and have been the subject of recent publications [ 5 , 6 , 7 , 8 ]. However, the global situation of genetic counseling research, as well as trends and subjects of broad interest in this area throughout the last 70 years, have not been adequately covered since the focus was mainly on specific journals [ 5 ] or countries [ 6 , 7 , 8 ]. We, therefore, mapped genetic counseling research globally using the Scopus database and the VOSviewer tool to provide academics and practitioners in this field, information on the scientific landscape as well as important and emerging themes.

Materials and methods

Search strategy.

The literature was searched and retrieved from the Scopus database on January 19, 2022. The Scopus database is regarded as one of the most significant and exhaustive collections of scientific information in the world [ 9 ]. The following search string was used in the article title: “genetic counsel*ing”. All document types written in the English language and released between 1952 and 2021 were included, except for erratum. The retrieved documents were subjected to bibliometric analysis using VOSviewer.

Publication outputs

A total of 3505 documents were retrieved. The most common document type was original articles (2515, 71.8%), followed by review articles (341, 9.7%). Letters, book chapters and conference papers, each contributed about 4.7–4.8% of the documents. Notes, editorials, short surveys and books contributed about 4.4% in total. From 1952 to 1967, the document number was one digit. From 1968 to 2010, the number of papers increased to two digits; from 2011 to 2021, it was three digits (Fig.  1 ).

Trends in the number of publications from 1952 to 2021 in the field of genetic counseling.

The top genetic counseling journals published 1163 documents, accounting for 33.2 per cent of all publications (Table  1 ). The Journal of Genetic Counseling had 587 publications with a Cite-Score of 3.8 and SJR 2020 of 0.867. Only three journals, the American Journal of Human Genetics, Genetics in Medicine, and Journal of Medical Genetics, have an SJR greater than two. The Scopus database has discontinued its coverage of the two of the top journals, while the American Journal of Medical Genetics has been renamed the American Journal of Medical Genetics, Parts A, B, and C.

Author Keywords

Network visualization of keyword co-occurrence map was constructed with a threshold of nine keyword co-occurrences in VOSviewer. The top keywords ranked by frequency were ‘genetic counseling’ ( n  = 1156), ‘genetic testing’ ( n  = 205), ‘prenatal diagnosis’ ( n  = 104), ‘breast cancer’ ( n  = 97), ‘genetic counselor’ ( n  = 68), ‘genetics’ ( n  = 59), ‘brca1’ ( n  = 49), ‘education’ ( n  = 48), ‘brca2’ ( n  = 45), and ‘hereditary cancer’ ( n  = 44).

To identify themes in the literature, we studied the terms in each cluster. Five clusters appear from the map in Fig.  2A with the following themes: genetic testing (red cluster), cancer (green cluster), genetic counselor (blue cluster), prenatal diagnosis (yellow cluster) and psychiatry (purple cluster). The overlay visualization of keyword co-occurrence map indicates the publishing dates when specific topics were most popular. Many newer keywords (yellow nodes) were found mainly in the blue cluster (genetic counselor theme) compared to other clusters (Fig.  2B ).

A Network visualization, B Overlay visualization.

The increasing number of publications per year may indicate the development trend in the field of genetic counseling. The observed trend may be attributable to the rapid evolution of clinical genetic services [ 5 , 6 , 7 , 8 ]. Genetic counselors collaborate with geneticists and other medical specialists to provide genetic counseling services. Genetic counseling research, which strives to improve the quality and availability of genetic counseling services, benefits from these clinical data. Original articles contributed to a large proportion of the publication outputs and increased significantly over the last decade. This finding indicates that the field is expanding in line with the development of genomic medicine [ 10 ]. Funding for implementation and outcome research is urgently needed to expand the scientific evidence for genetic counseling practice [ 10 ].

The present analysis revealed that 1163 documents or 33.2% of studies were published in the top 10 journals. Of these, more than half of the relevant documents were published in the Journal of Genetic Counseling . This indicates that this is the most active journal publishing a large number of documents and has a substantial impact on the field of genetic counseling. Among the top journals, the results revealed only three journals have SCImago Journal Rank (SJR) greater than two; the American Journal of Human Genetics, Genetics in Medicine , and Journal of Medical Genetics . As a result, it can be deduced that approximately 170 documents, or 4.9% of all genetic counseling publications, were published in high-impact journals.

The keyword co-occurrence map identified five major clusters in the genetic counseling field (Fig.  2A ). These are genetic testing (red cluster), cancer (green cluster), genetic counselor (blue cluster), prenatal diagnosis (yellow cluster) and psychiatry (purple cluster) themes. Some of these topics (cancer and prenatal) have earlier been identified by content analysis study [ 5 ]. Genetic counseling should be regarded as an integral part of the genetic testing process [ 11 ]. Thus, genetic testing appeared as the main theme with the largest cluster. There are several categories of genetic testing that require genetic counseling. In diagnostic genetic testing, the test is performed on symptomatic individuals. While pre-test genetic counseling may not always be necessary, post-test genetic counseling should be offered especially when the result is positive. Conversely, pre-and post-test genetic counseling should be offered in other types of genetic testing such as predictive, susceptibility (risk), carrier, prenatal, preimplantation genetic diagnosis (PGD), and genetic screening. For pharmacogenetic testing, the need for genetic counseling will depend on whether the results have other implications rather than decisions about drug treatment [ 11 ].

The second theme in the genetic counseling field is cancer. Pathogenic variants in genes can be broadly grouped into sporadic, familial, and hereditary cancers. Sporadic cancers, making up 75–80% of all cancers, are caused by acquired mutations in tumour cells. About 10–20% of cancers are familial but not caused by a gene mutation. On the other hand, familial cancers are attributed to shared family factors. Finally, hereditary cancer is evaluated when a person has a maternal or paternal family history with suggestive symptoms, depending on the type of cancer and specific hereditary syndrome. More studies are needed to build a cancer genetic counseling service to enable fair access for all patients [ 12 ]. In order to establish a cancer genetic counseling service, more studies are needed to look into the requirements and obstacles of patients, family members, and specialists particularly, in different settings/countries to ensure equitable access to all patients [ 12 ].

Genetic counselor, the third theme, is a health practitioner who has been trained to evaluate genetic testing results, both scientifically and medically, while also considering psychological, ethical, and family concerns [ 13 ]. The genetic counselor theme has the highest number of recent keywords based on the number of yellow nodes (Fig.  2B ). These keywords with the average publication year 2018 onwards include ‘covid-19’, ‘underrepresented population’, ‘service delivery models’, ‘workforce’, ‘disparities’, ‘service delivery’, ‘professional development’, ‘cultural competence’, ‘access’, ‘diversity’, ‘telemedicine’ and ‘health literacy’. These keywords are related to the genetic counselors’ challenges and needs related to genetic service delivery models.

The fourth theme in the genetic counseling field is prenatal diagnosis. The need for prenatal genetic counselling is increasing worldwide due to advances in prenatal screening and diagnostic tests [ 14 ]. Given the complexity of genetic testing information, the role of genetic counseling at pre-and post-test is to increase knowledge, decrease anxiety, avoid decisional conflicts, and aid in the interpretation of test results, thereby helping an individual make an informed decision [ 14 , 15 ].

The last theme in the genetic counseling field is psychiatry. Psychiatric genetic counseling has benefits for people with psychiatric disorders and their families despite the limited genetic testing available [ 16 , 17 , 18 ]. The role of genetic counseling is to help people understand that mental illness is not their fault, but there are things that they can do to protect their mental health [ 19 ]. It is an emerging speciality within clinical genetics [ 20 ].

The main limitation of our study is that, despite Scopus’ vast coverage [ 9 ], we might have overlooked some important studies in other databases. Second, new research is being released almost daily, and the data in this analysis was up to January 19, 2022. Third, we might have missed several relevant documents if the authors had not included the term “genetic counseling” in the article titles. Lastly, the research themes in this study were derived from keyword co-occurrence thematic analysis without a deeper analysis.

Conclusions

The field of genetic counseling is growing as genomic medicine develops. Genetic counseling research has identified the following themes: genetic testing, cancer, genetic counselor, prenatal diagnosis, and psychiatry. Future directions in genetic counseling research may be related to the requirements and challenges of genetic counselors, according to the emerging topics.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, 16150, Kelantan, Malaysia

Wan Nur Amalina Zakaria

Cancer Research Malaysia, 47500, Subang Jaya, Selangor, Malaysia

Sook-Yee Yoon

Department of Health Information Management, Universitas Indonesia Maju, Jakarta, Indonesia

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Asma Hayati Ahmad & Rahimah Zakaria

Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia

Zahiruddin Othman

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WNAZ designed the study; RZ and AW contributed to data extraction and prepared the first draft of the manuscript; and all authors reviewed and provided feedback on the manuscript.

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Zakaria, W.N.A., Yoon, SY., Wijaya, A. et al. Global trends and themes in genetic counseling research. Eur J Hum Genet 31 , 1181–1184 (2023). https://doi.org/10.1038/s41431-023-01371-3

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Received : 13 October 2022

Revised : 03 April 2023

Accepted : 20 April 2023

Published : 04 May 2023

Issue Date : October 2023

DOI : https://doi.org/10.1038/s41431-023-01371-3

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