Identification of Compound Heterozygous CYP11A1 Variants via Reanalysis of Clinical Sequencing Data

A molecular diagnosis is currently achievable in approximately 50% of patients assessed by clinical geneticists at tertiary care centres. Next‐Generation Sequencing Panels contain a defined group of genes associated with a clinically defined set of phenotypes. Most clinical sequencing providers streamline their wet‐bench workflows by sequencing the entire exome or genome, followed by targeted bioinformatic extraction of variant data from a pre‐specified gene set. Thus, additional data on these patients remain available but are only reviewed by special request. We interrogated clinical‐grade sequencing data on two out of three affected members of a family with childhood‐onset adrenal insufficiency in whom an autosomal recessive condition was suspected. Review of clinome data identified heterozygosity for CYP11A1 variants c.644T>C; p.(Phe215Ser) and c.1187G>A; p.(Arg396Lys) in both affected sibs. Long‐read whole genome sequencing of the proband showed these variants were in trans , confirming compound heterozygosity and resolving the molecular etiology of the clinical diagnosis.