Journal Article

Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations

Retterer, Kyle, Sheridan, Eamonn, Hurles, Matthew E., Reversade, Bruno, Chundru, V. Kartik, Lindsay, Sarah J., Bertoli-Avella, Aida, Malawsky, Daniel S., Ayaz, Akif, Szenker-Ravi, Emmanuelle, Gardner, Eugene J., Türkdoğan, Dilşad, Danecek, Petr, Akbeyaz, Ismail Hakki, Martin, Hilary C., Guillen Sacoto, Maria J., Ólafsdóttir, Hildur, Zhang, Zhancheng, Al Balushi, Aaisha Ibrahim, Wright, Caroline F., Firth, Helen V., Samocha, Kaitlin E., Walter, Klaudia, McWalter, Kirsty, Ustach, Vincent D., Wigdor, Emilie M., Eberhardt, Ruth Y., Bauer, Peter, Torene, Rebecca

2024

Overview

Autosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2–19% across genetically inferred ancestry groups and was significantly correlated with average autozygosity. Established autosomal recessive developmental disorder-associated (ARDD) genes explained 84.0% of the total autosomal recessive coding burden, and 34.4% of the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. Statistical analyses identified two novel ARDD genes: KBTBD2 and ZDHHC16 . This study expands our understanding of the genetic architecture of developmental disorders across diverse genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes. Analysis of autosomal recessive coding variants in 29,745 trios from the DDD study and GeneDx provides insights into the genetic architecture of developmental disorders across ancestrally diverse populations.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/212 / 631/208/2489 / 631/208/366 / Acyltransferases - genetics / Agriculture / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cohort Studies / Developmental disabilities / Developmental Disabilities - genetics / Disorders / Exome - genetics / Female / Gene Function / Genes / Genes, Recessive / Genetic analysis / Genetic diversity / Genetic Predisposition to Disease / Genetic Variation / Genomes / Genotype & phenotype / Hereditary diseases / Human Genetics / Humans / Male / Mutation / Mutation, Missense / Quality control / Statistical analysis