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 copy-number variations 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) modeling 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, having among them 8 with an Online Mendelian Inheritance in Man AR annotation. Deletions of , followed by , both within segmental duplications, were the only recurrent findings explaining phenotypes in a total of 10 and 3 patients, respectively. Recurrent heterozygous deletions were detected in 0.3%-0.5% of controls. We reviewed "knockout" patients for the remaining 29 genes without disease associations and identified as a likely novel cause for AR rod-cone dystrophy in 4 families.

CONCLUSION

A tailored copy-number variations analysis of genome sequencing trio data shows that biallelic inherited gene deletions are rare, with biallelic deletions causing nephronophthisis the leading finding. We propose as a novel cause for AR retinopathy.