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The Role of Recessive Genetic Variants in Developmental Disorders

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Scientists have conducted the largest and most diverse study to date on how recessive genetic changes contribute to developmental disorders. They found that most undiagnosed cases that are due to recessive causes are linked to genes we already know about, and suggest a shift in research focus could improve diagnosis rates.


Researchers from the Wellcome Sanger Institute and their collaborators at GeneDx analyzed genetic data from nearly 30,000 families affected by developmental disorders – six times more families with greater diversity in ancestral backgrounds compared to previous work.


While discovering several genes that were previously not linked to these conditions, researchers found that known genes explain over 80 percent of cases caused by recessive genetic variants. This is a significant increase from previous estimates. The study also revealed the contribution of recessive genetic variants to developmental disorders varies significantly across the ethnic groups studied.

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The findings, published today (23 September) in Nature Genetics, shed new light on the genetic basis of developmental disorders, and highlight the importance of considering a person’s genetic background in diagnosis and research.


The team suggests that efforts to discover recessive genes associated with these disorders in the last few years have been largely successful and that the challenge now lies more in interpreting genetic changes in known recessive genes. Using this approach could potentially be used to diagnose twice as many patients compared to focusing solely on remaining gene discovery, they say.


Many developmental disorders, which can impact a child’s physical, intellectual, or behavioral development, have genetic origins. Some are caused by recessive genes, where a child must inherit an altered gene copy from both parents to develop the condition. They include Joubert syndrome, Bardet-Biedl syndrome and Tay-Sachs disease. Until now, overall quantification of these recessive genetic causes across diverse populations has not been done.


In this new study, researchers combined summarised data from the Deciphering Developmental Disorders (DDD) study and GeneDx cohorts to identify individuals with similar genetic backgrounds, totaling 29,745 families. Over 20 percent of these families were from mostly non-European ancestries. Analyzing this large dataset provided more insight, especially for smaller and less-studied groups.


The team found the number of patients affected by recessive genetic variants varied greatly between different ancestry groups, ranging from two to 19 percent of cases. This variation is strongly linked to the prevalence of unions between close relatives – consanguinity – in these groups.


Researchers identified several genes, including KBTBD2CRELD1 and ZDHHC16, newly associated with developmental disorders, providing answers for previously undiagnosed families. They also estimate that around 12.5 percent of patients may have multiple genetic factors contributing to their condition, highlighting the complexity of these disorders.


Importantly, they found known genes explain about 84 percent of cases caused by recessive genetic variants, which was similar across individuals from European and non-European ancestry groups. This substantial increase from previous estimates suggests that the new recessive genes that have been discovered over the last few years account for a substantial fraction of previously undiagnosed patients with recessive causes. However, the scientists found that there are likely still diagnoses being missed in these known genes that involve DNA changes that are difficult to interpret. The findings emphasize the importance of improving interpretation of harmful genetic variants in known disease-causing genes.


Reference:

Chundru VK, Zhang Z, Walter K, et al. Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations. Nat Genet. 2024. doi: 10.1038/s41588-024-01910-8


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