We estimated the genome-wide contribution of recessive coding variation from 6,040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared to 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, due to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed non-consanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F, KDM5B, and THOC6. EIF3F is a novel disease gene, and KDM5B 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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The objective of this study was to investigate variation in sperm quality metrics (motility, velocity, linearity, longevity, and density) of hatchery‐reared Lake Trout Salvelinus namaycush throughout the spawning season. Seasonal variation in sperm quality was investigated using both a regression and repeated‐measures approach. Sperm was collected from the same 16 individuals over four sampling periods, separated by 3‐week intervals. Regression analyses showed that 7–27% of the variation in sperm traits could be explained by seasonal variation, indicating that seasonality can have a significant impact on the quality of sperm. Significant positive linear relationships were found for percent motility and linearity at 5 s postactivation. Significant negative quadratic relationships were found for velocity at 5 s postactivation, longevity, and density, whereas a positive quadratic relationship was found for linearity at 10 s postactivation. Repeated measures ANOVAs showed a significant effect of season for percent motility and linearity at 5 and 10 s postactivation, velocity at 10 s postactivation, and longevity. Our findings are important for optimizing fertilization protocols for hatchery production and can also be used to understand reproductive biology and ecology of wild Lake Trout stocks.