Known genes account for most undiagnosed cases of developmental disorders

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 per cent 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.

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

Importantly, they found known genes explain about 84 per cent 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 interpret³. The findings emphasize the importance of improving interpretation of harmful genetic variants in known disease-causing genes.

Dr Kartik Chundru, first author of the study, formerly at the Wellcome Sanger Institute and now University of Exeter, said: “These gene discoveries will provide answers for some previously undiagnosed families and help clinicians better understand and identify these conditions. Our study highlights the importance of reanalyzing genetic data with updated methods and knowledge, as it can lead to new diagnoses for patients without needing additional samples.”

Dr Hilary Martin, senior author of the study at the Wellcome Sanger Institute, said: “One of the surprising findings from this work was that many patients with one known genetic diagnosis might actually have additional rare genetic changes contributing to their condition. Identifying these additional changes could improve our understanding of the patient’s condition, lead to more accurate diagnoses, and potentially offer new treatment options. It also highlights the complexity of genetic disorders and the need for comprehensive genetic analysis.”

Source:

Wellcome Trust Sanger Institute

Journal reference:

Chundru, V. K., et al. (2024) Federated analysis of the contribution of autosomal recessive coding variants to 29,745 developmental disorder patients from diverse populations. Nature Genetics. doi.org/10.1038/s41588-024-01910-8.