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.