Genotype-phenotype correlation in partial combined 17α-hydroxylase/17,20-lyase deficiency: functional characterization of CYP17A1 variants in ten 46,XY patients.

CYP17A1

Biallelic CYP17A1 variants retaining residual enzyme activity; novel splice-site variants and founder allele c.1263G>A

This study describes ten 46,XY patients from nine families with partial combined 17α-hydroxylase/17,20-lyase deficiency, using long-read CYP17A1 sequencing, minigene splicing assays and enzyme activity measurements in HEK293T cells. All showed the triad of elevated mineralocorticoid precursors, generalised androgen suppression and preserved cortisol; median age at diagnosis was 17.5 years, with hypertension in 3 of 10 and hypokalaemia in 2 of 10. Ten distinct variants were found, including two novel splice-site variants (c.666+2T>C, c.1243+2T>G), and the c.1263G>A allele, carried on a shared haplotype by 5 patients, indicates a Chinese founder effect. Four uncharacterised variants retained 11–28.9% 17α-hydroxylase and 6.3–22.6% 17,20-lyase activity, yet two patients with identical genotypes had opposite genital phenotypes: hypospadias in one, raised male, and complete female external genitalia in the other, raised female.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The clinical message is twofold: residual CYP17A1 activity broadly explains the degree of virilisation, but the same genotype can lead to a different sex of rearing, so the genital phenotype cannot be predicted from genotype alone, whether in genetic counselling or prenatally. The small sample (ten patients) limits the reach of the proposed correlations. A median age at diagnosis of 17.5 years is a reminder that this diagnosis is often made late.

Analysis by Dr Thibaut Benquey