Objective Human phenotype ontology (HPO) terms are increasingly attached to large-scale genomic datasets but have not yet been exploited to detect undiagnosed congenital adrenal hyperplasia (CAH). We asked whether clustering CAH-relevant HPO terms could yield a ‘suggested’ CAH cohort within the 100 000 Genomes Project (100kGP) and what proportion of these individuals harbour known coding variants in CAH-related genes. Results 22 phenotype groups were distilled from CAH literature and mapped to 104 HPO terms. Seven 100kGP participants carrying an HPO term explicitly denoting CAH formed a reference cohort of confirmed cases. Filtering for ≥3 phenotype groups identified 40 additional participants (suggested cases). Group representation was highly skewed: recorded abnormalities in growth (28/40), metabolism (23/40) and connective-tissue (20/40) predominated, whereas salt-wasting and androgen-biochemistry features were entirely absent. Screening of CYP21A2 , CYP11B1 , CYP17A1 , HSD3B2 , POR , STAR and CYP11A1 revealed only two missense variants across all 47 combined cases: homozygous rs6467 within CYP21A2 and heterozygous rs151258756 within HSD3B2 . Given that previous CAH literature suggests that most cases are caused by traditional coding variants in these genes (in particular, within CYP21A2 ), these findings may question the effectiveness of using HPO terms and groupings to derive a case cohort. Ultimately, this approach merits further evaluation against clinical data. In the meantime, alternative methods using other recorded observations data or genotype-first approaches should be considered in the context of CAH.
Gee et al. (Fri,) studied this question.