Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation

Abstract

Abstract We devised a new method (Chameleolyser) that accurately identifies single nucleotide variants (SNVs), copy number variants and ectopic gene conversion events in duplicated genomic regions using whole-exome sequencing (WES) data. Application to a cohort of 41,755 WES samples yielded 20,432 rare homozygous deletions and 2,529,791 rare SNVs, of which we can show that 338,084 are due to gene conversion events. None of the SNVs are detectable using regular analysis techniques. Validation by high-fidelity long-read sequencing in 20 samples confirmed >88% of called variants. Focusing on variation in known disease genes led to a direct molecular diagnosis in 25 previously undiagnosed patients. Our method can readably be applied to existing WES data.