Phenotypic and molecular characteristics in eleven Chinese patients with 5α‐reductase Type 2 deficiency

Summary Context Steroid 5α‐reductase type 2 deficiency (5α‐ RD 2) is a male‐limited, autosomal recessive inherited disease. Affected 46, XY individuals usually present with ambiguous genitalia at birth. An early and precise diagnosis is of great value to the long‐term prognosis of the disease. Objective To describe the clinical features and molecular determinants in 11 Chinese patients with the SRD 5A2 gene mutation and to investigate the functional alteration arising from a novel splicing site mutation identified in one of the patients. Subjects and Methods Eleven subjects born with abnormal external genitalia from 10 unrelated families were recruited. Among them, nine patients who were reared as girls underwent virilization and gender change after puberty. Genotyping analysis of the SRD 5A2 gene was performed in each of the patients. Haplotype analysis was performed in five patients with a prevalent mutation of p.G203S to illustrate the founder effect in China. Functional impairment of the new variant was explored by an in vitro splicing study and enzymatic activity assay. Results Nine mutations in the SRD5A2 gene were detected in the eleven patients. In addition to the previously reported p.G203S, p.R227Q, p.N193S, p.R246Q, p.Q6X, p.A228V, c.655delT and IVS1‐2 A>G, a novel splicing site mutation (IVS4 + 2 T>C) was identified. From an in vitro functional study, this mutation was found to result in a skipping of exon 4 in the course of mRNA splicing, leading to a truncated protein of 205 amino acids that lacks the catalysing activity. Two siblings with the same compound heterozygous mutation (IVS1‐2A>G/p.G203S) exhibited differing phenotypes and opposite patterns of gender rearing. A prevalent variation p.V89L combined with c.655delT was revealed to cause a mild phenotype of 5α‐RD2 with a micropenis. Conclusion This cohort study describes the phenotypic, biochemical and long‐term outcome in 11 Chinese patients with 5α‐ RD 2 deficiency and defines the genotypic spectrum of SRD 5A2 mutations in China.