Copy number analysis from genome sequencing data of 11,754 rare disease parent-child trios: a model for identifying autosomal recessive human gene knockouts including a novel gene for autosomal recessive retinopathy

Purpose In parent-child trios with genome sequencing data, we investigated inherited biallelic deletions to identify known and novel genetic disorders. Methods We developed a CNV analysis pipeline based on autosomal genome sequencing read depth of Genomics England 100,000 Genomes Project data from 11,754 parent-child trios and additional 18,875 non-trios. A control cohort of 15,440 cancer patients provided independent deletion frequencies. Results Autosomal recessive (AR) modelling detected 34 distinct rare deletions that were homozygous in the proband and heterozygous in both parents. These inherited biallelic deletions were only detected in 52 trios. These “knockout” regions included 37 genes among them 8 with an OMIM AR annotation. Deletions of NPHP1, followed by OTOA, both within segmental duplications, were the only recurrent findings explaining phenotypes in a total of 10 and 3 patients, respectively. Recurrent heterozygous NPHP1 deletions were detected in 0.3%-0.5% of controls. We reviewed “knockout” patients for the remaining 29 genes without disease associations and identified SLC66A1 as a likely novel cause for AR rod-cone dystrophy in 4 families. Conclusion A tailored CNV analysis of genome sequencing trio data shows that biallelic inherited gene deletions are rare, with NPHP1 biallelic deletions causing nephronophthisis the leading finding. We propose SLC66A1 as a novel cause for AR retinopathy.