Publication
Federated analysis of the contribution of recessive coding variants to 29,745 developmental disorder patients from diverse populations
Publisher:
Cold Spring Harbor Laboratory
Date:
24-07-2023
DOI:
10.1101/2023.07.24.23293070
Abstract: Autosomal recessive (AR) coding variants are a well-known cause of rare disorders. We quantified the contribution of these variants to developmental disorders (DDs) in the largest and most ancestrally erse s le to date, comprising 29,745 trios from the Deciphering Developmental Disorders (DDD) study and the genetic diagnostics company GeneDx, of whom 20.4% have genetically-inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide AR coding variants ranged from ∼2% to ∼18% across genetically-inferred ancestry groups, and was significantly correlated with the average autozygosity (r=0.99, p=5x10 -6 ). Established AR DD-associated (ARDD) genes explained 90% of the total AR coding burden, and this was not significantly different between probands with genetically-inferred European versus non-European ancestries. Approximately half the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. We estimated that ∼1% of undiagnosed patients in both cohorts were attributable to damaging biallelic genotypes involving missense variants in established ARDD genes, highlighting the challenge in interpreting these. By testing for gene-specific enrichment of damaging biallelic genotypes, we identified two novel ARDD genes passing Bonferroni correction, KBTBD2 (p=1x10 -7 ) and CRELD1 (p=9x10 -8 ). Several other novel or recently-reported candidate genes were identified at a more lenient 5% false-discovery rate, including ZDHHC16 and HECTD4 . This study expands our understanding of the genetic architecture of DDs across erse genetically-inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may allow us to diagnose more patients than discovering the remaining genes.