Autosomal recessive coding variants explain only a small proportion of undiagnosed developmental disorders in the British Isles
Abstract
We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study to search for recessive coding diagnoses. We estimated that the proportion of cases attributable to recessive coding variants is 3.6% for patients of European ancestry, and 30.9% for those of Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes, and found that known recessive genes showed a significant tendency towards having lower p-values (Kolmogorov-Smirnov p=3.3×10−16). Three genes passed stringent Bonferroni correction, including a new disease gene, EIF3F, and KDM5B, which has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.
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