Sarah L. Wynn

The United Nations, 2021 resolution to promote and protect the human rights of the estimated 300 million People Living with a Rare Disease and their families, set a milestone worldwide. At the same time, the successful diagnostic results of large genomic initiatives are reshaping rare disease healthcare in many countries. However, increasing diagnostic capability does not necessarily translate into improved care. Patients, families, and healthcare professionals navigate challenges in variant interpretation and prognosis, uneven access to specialist expertise and follow‐up, limited natural history information and therapeutic options, and the wider familial and reproductive implications of genomic findings. Healthcare systems also face challenges related to workforce and service capacity, data governance, equity, research sustainability, and the integration of genomic technologies into longitudinal care. Drawing on published evidence, patient‐organization experience and illustrative clinical scenarios, we argue that the value of genomic medicine for rare disease should be assessed beyond diagnostic yield alone and across individual, clinical and societal levels. Our vision for the future includes accessible education for families and professionals, multidisciplinary and longitudinal rare disease services embedded within publicly funded healthcare, sustainable research and data‐sharing frameworks, partnership with patient advocacy organizations, and meaningful representation of people living with rare disease in governance, research, and innovation.

Unique is a UK-based charity that serves a global community of people and families affected by rare chromosome and gene disorders predominantly associated with developmental delay and/or intellectual disability. It aims to provide knowledge and support from the moment of diagnosis throughout a person’s lifetime. Unique has a community of over 35,000 members worldwide, based in 135 countries. Whilst diagnoses vary, myriad experiences of living with rare chromosome and gene disorders are shared by Unique members, from pregnancy to adulthood, providing an important source of insights, advice and support to individuals and families living similar lives under the care of different health services. This paper outlines the nature of support and information services provided by Unique and highlights key insights gleaned from direct engagement with its members. Unique’s services work in partnership with clinical care but also contribute to the broader understanding of lived experiences, unmet needs and opportunities for improved service delivery.

Background: Social media groups (SMGs) enable individuals with rare diseases to connect with one another and access instant support and advice. Accelerated diagnoses of genetic neurodevelopmental disorders (NDDs) over the last decade have driven rapid expansion of gene-specific SMG membership. Limited literature regarding parental use of SMGs in the context of managing their child’s NDD exists. Objective: The objective of our study was to determine and describe how parents use social media and the internet in the context of their child’s NDD. Methods: We undertook a mixed methods study of 477 parents within a cohort of children with NDDs (Genetic Rare Disease: Observational Cohort Study; GenROC). A total of 359 parents provided quantifiable survey responses regarding their use of social media. We also interviewed 17 parents to understand how they use SMGs and their views on the data held within these groups. Results: Our survey found 359/475 (75.7%) of parents use SMGs related to their child’s genetic disorder, and of these, 98.5% (354/359) are on Facebook. Most SMGs are closed, international, have more than 200 members, are specific to the NDD, and are associated with a corresponding charity or foundation. In total, 191/312 (61.2%) parents could not recall what they had consented to when joining the group with respect to the use of their posted data. Most parents trust the data (Likert scale 1‐10; mean 7.03, SD 1.98) that are shared but acknowledged the anecdotal nature of them. Parents found the most valuable element of the SMG to be shared lived experience with other families. Interview data from 17 parents were coded and analyzed thematically. A total of 4 main themes were identified: (1) SMGs for support and shared lived experience; (2) possible harms from participation in SMGs; (3) SMG composition, demographics, and dynamics; and (4) usefulness and use of data shared within the groups. Conclusions: This mixed methods study shows the evolving landscape of SMG use in neurodevelopmental disorders, highlights its benefits and downsides, and is widely applicable to all parent SMGs for specific niche medical conditions. Using the strength of these groups in a more collaborative approach in the future could prove useful to clinicians, families, and researchers alike.

SUMMARY: Availability and implementation of genetic testing on a national and global level have advanced exponentially over the last few decades. While having a diagnosis of a rare genetic condition can have a plethora of effects on those concerned, the delivery of a diagnosis can often be accompanied by little information and no obvious care path for the future.Continued advancements in genomics have curtailed often lengthy diagnostic odysseys but also highlighted inequities and the need for extended support and provision of related information.Unique, a UK‐based charity serving the global community of people and families affected by rare chromosome and gene disorders associated with developmental delay and/or intellectual disability, aims to bridge the knowledge and care gap between diagnosis and follow‐up care.Bringing together patients, families, research scientists, clinical geneticists and other professionals involved in the care of individuals with a rare genetic condition can have a powerful impact on the progress of targeted support.With a community of over 30,000 member families, sharing knowledge and experience of rare genetic disorders, and also experiences of diagnosis delivery and follow‐up care, this community provides an important source of insights and actionable concerns of those experiencing a rare disease journey, from diagnosis and throughout life.

Prenatal sequencing tests are being introduced into clinical practice in many developed countries. In part due to its greater ability to detect genetic variation, offering prenatal sequencing can present ethical challenges. Here we review ethical issues arising following the implementation of prenatal sequencing in the English National Health Service (NHS). We analysed semi structured interviews conducted with 48 parents offered prenatal sequencing and 63 health professionals involved in delivering the service to identify the ethical issues raised. Two main themes were identified: (1) Equity of access (including issues around eligibility criteria, laboratory analytical processes, awareness and education of clinicians, fear of litigation, geography, parental travel costs, and access to private healthcare), and (2) Timeliness and its impact on parental decision-making in pregnancy (in the context of the law around termination of pregnancy, decision-making in the absence of prenatal sequencing results, and the “importance” of prenatal sequencing results). Recognising both the practical and systemic ethical issues that arise out of delivering a national prenatal sequencing service is crucial. Although specific to the English context, many of the issues we identified are applicable to prenatal sequencing services more broadly. Education of health professionals and parents will help to mitigate some of these ethical issues.

Haploinsufficiency for SOX9, the master chondrogenesis transcription factor, can underlie campomelic dysplasia (CD), an autosomal dominant skeletal malformation syndrome, because heterozygousSox9null mice recapitulate the bent limb (campomelia) and some other phenotypes associated with CD. However, in vitro cell assays suggest haploinsufficiency may not apply for certain mutations, notably those that truncate the protein, but in these cases in vivo evidence is lacking and underlying mechanisms are unknown. Here, using conditional mouse mutants, we compared the impact of a heterozygousSox9null mutation (Sox9^+/−) with theSox9^+/Y440XCD mutation that truncates the C-terminal transactivation domain but spares the DNA-binding domain. While someSox9^+/Y440Xmice survived, allSox9^+/−mice died perinatally. However, the skeletal defects were more severe and IHH signaling in developing limb cartilage was significantly enhanced inSox9^+/Y440Xcompared withSox9^+/−. ActivatingSox9^Y440Xspecifically in the chondrocyte–osteoblast lineage caused milder campomelia, and revealed cell- and noncell autonomous mechanisms acting on chondrocyte differentiation and osteogenesis in the perichondrium. Transcriptome analyses of developingSox9^+/Y440Xlimbs revealed dysregulated expression of genes for the extracellular matrix, as well as changes consistent with aberrant WNT and HH signaling. SOX9^Y440Xfailed to interact with β-catenin and was unable to suppress transactivation ofIhhin cell-based assays.We propose enhanced HH signaling in the adjacent perichondrium induces asymmetrically localized excessive perichondrial osteogenesis resulting in campomelia. Our study implicates combined haploinsufficiency/hypomorphic and dominant-negative actions of SOX9^Y440X, cell-autonomous and noncell autonomous mechanisms, and dysregulated WNT and HH signaling, as the cause of human campomelia.

The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 ( SOX9 ) and SOX10 ( SOXE ) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia SOX9 ^Y440X mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that SOX9 ^Y440X causes deafness via distinct mechanisms in the endolymphatic sac (ES)/duct and cochlea. By contrast, conditional heterozygous Sox9 -null mice are normal. During the ES development of Sox9 ^Y440X/+ heterozygotes, Sox10 and genes important for ionic homeostasis are down-regulated, and there is developmental persistence of progenitors, resulting in fewer mature cells. Sox10 heterozygous null mutants also display persistence of ES/duct progenitors. By contrast, SOX10 retains its expression in the early Sox9 ^Y440X/+ mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9 ^Y440X is implicated in impairing the normal cooperation of SOX9 and SOX10 in repressing the expression of the water channel Aquaporin 3, thereby contributing to endolymphatic hydrops. Our study shows that for a functioning endolymphatic system in the inner ear, SOX9 regulates Sox10 , and depending on the cell type and target gene, it works either independently of or cooperatively with SOX10. SOX9 ^Y440X can interfere with the activity of both SOXE factors, exerting effects that can be classified as haploinsufficient/hypomorphic or dominant negative depending on the cell/gene context. This model of disruption of transcription factor partnerships may be applicable to congenital deafness, which affects ∼0.3% of newborns, and other syndromic disorders.