Researchers examined how recessive genetic variants influence developmental disorders, proposing that reevaluating genetic data might enhance the understanding and diagnosis of these conditions for millions of families globally.
A team of scientists has carried out the largest and most varied study so far concerning the impact of recessive genetic mutations on developmental disorders1. Their findings indicate that many undiagnosed cases linked to recessive causes are associated with already recognized genes, and they recommend shifting research priorities to improve diagnosis rates.
Scientists from the Wellcome Sanger Institute and their partners at GeneDx evaluated genetic data from close to 30,000 families impacted by developmental disorders—this number is six times higher and includes a wider range of ancestral backgrounds compared to earlier studies.
In addition to identifying several genes that were not previously associated with these disorders, the researchers discovered that known genes account for over 80 percent of cases caused by recessive genetic variants, a notable increase from earlier estimates2. The research also highlighted that the extent to which recessive genetic variants contribute to developmental disorders varies greatly among the different ethnic groups examined.
The results, released today (23 September) in Nature Genetics, provide important insights into the genetic underpinnings of developmental disorders, emphasizing the need to take a person’s genetic background into account during diagnosis and research.
The team suggests that recent efforts to identify recessive genes tied to these disorders have yielded considerable success and that the current challenge lies in interpreting the genetic variations in known recessive genes. They believe that this method could potentially double the number of patients diagnosed compared to focusing solely on identifying unknown genes3.
Many developmental disorders, which can affect a child’s physical, cognitive, or behavioral growth, have genetic roots. Some of these conditions arise from recessive genes, where a child must inherit a mutated gene from both parents to manifest the disorder. Notable examples include Joubert syndrome, Bardet-Biedl syndrome, and Tay-Sachs disease. Until now, there has been no comprehensive measurement of these recessive genetic causes across various populations.
In this study, researchers merged summarized data from the Deciphering Developmental Disorders (DDD) study4 and GeneDx groups to find individuals with comparable genetic backgrounds, totaling 29,745 families. Over 20 percent of these families originated primarily from non-European ancestries. Analyzing this expansive dataset provided deeper insights, particularly for smaller, less-researched groups.
The team observed considerable variation in the proportion of patients affected by recessive genetic variants among different ancestry groups, ranging from two to 19 percent of cases. This discrepancy is closely associated with the frequency of marriages between close relatives—consanguinity—within these populations.
Researchers pinpointed several new genes, such as KBTBD2, CRELD1, and ZDHHC16, linked to developmental disorders, offering explanations for families who had previously gone undiagnosed. They also estimate that around 12.5 percent of patients may exhibit several genetic factors contributing to their condition, underscoring the complexity of these disorders.
Crucially, they found that known genes account for roughly 84 percent of cases linked to recessive genetic variants, showing consistency between individuals from both European and non-European ancestry groups5. This notable increase from prior estimates implies that the newly identified recessive genes discovered in recent years represent a significant portion of previously undiagnosed cases attributed to recessive causes. Nonetheless, the researchers noted that some diagnoses may still be overlooked in these known genes due to difficult-to-interpret DNA changes3. The findings stress the necessity of enhancing the interpretation of harmful genetic mutations in recognized disease-causing genes.
Dr. Kartik Chundru, the lead author of the study, previously at the Wellcome Sanger Institute and now at the University of Exeter, stated: “These gene discoveries will provide solutions for some families that have remained undiagnosed and assist clinicians in better understanding and identifying these conditions. Our research underscores the significance of reassessing genetic data with updated methods and insights, as this can result in new diagnoses for patients without needing additional samples.”
Dr. Vincent Ustach, a senior author of the study at GeneDx, remarked: “This study features the most diverse participant cohort ever analyzed regarding the role of recessive variants in developmental disorders, demonstrating the critical importance of a diverse dataset for achieving a more thorough understanding of developmental disorders across various ancestries. The findings from this research can lead to more personalized and actionable results for families with affected children and enhance our capacity to provide answers for underrepresented populations.”
Dr. Hilary Martin, another senior author of the study at the Wellcome Sanger Institute, mentioned: “One unexpected outcome of this research was finding that many patients with an established genetic diagnosis might actually have additional rare genetic changes that contribute to their condition. Identifying these additional variants could enhance our comprehension of the patient’s condition, improve diagnosis accuracy, and possibly introduce new treatment avenues. It also highlights the complexity of genetic disorders and the necessity for comprehensive genetic analysis.”
Notes:
- Some rare conditions, such as cystic fibrosis, Tay-Sachs disease, and spinal muscular atrophy, occur due to autosomal recessive genetic variants. “Autosomal” indicates that the gene involved is located on one of the non-sex chromosomes. “Recessive” means that two copies of the mutated gene—one from each parent—are needed to cause the disorder. In a family where both parents are carriers without having the disease, about a quarter of their children will inherit two copies of the mutation and develop the disorder.
- Earlier estimates of the impact of recessive variants on these disorders in known genes from 2018 reflect the progress made in discovering new disease genes since then.
H. Martin et al. (2018) ‘Quantifying the contribution of recessive coding variation to developmental disorders’ Science. DOI: 10.1126/science.aar6731
- From the genetic data, researchers approximated that there are around 280 potential diagnoses arising from protein-altering variants in known genes, compared to about 161 potential diagnoses from undiscovered genes.
- The Deciphering Developmental Disorders (DDD) study seeks to enhance clinical genetic practices for children with developmental disorders. Children were enrolled in the study from 2010 to 2015.The DDD study is no longer enrolling new patients. If your child has an undiagnosed developmental disorder, please consult with your pediatrician or GP regarding the most suitable tests or referrals to other studies.
The DDD team is committed to meticulously analyzing and re-analyzing all genomic data from families within the study over the next five years to strive for a diagnosis for as many children as possible.
- This observation holds true for individuals of both European and non-European ancestry (87 percent vs. 80 percent).
The data from the study can be accessed here: https://github.com/chundruv/DDD_GeneDx_Recessives
Funding: This research was funded by Wellcome and the National Institute for Health and Care Research Exeter Biomedical Research Centre. For a complete list of funding acknowledgments, please refer to the publication.
