New insights into 5α-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype-phenotype profiling of SRD5A2 in 190 Chinese patients

J Med Genet. 2019 Oct;56(10):685-692. doi: 10.1136/jmedgenet-2018-105915. Epub 2019 Jun 11.


Background: The 5α-reductase type 2 (5α-RD2) deficiency caused by mutations in the steroid 5α-reductase 2 (SRD5A2) gene results in variable degrees of undervirilisation in patients with 46,XY disorders of sex development. This study aims to profile the regional distribution and phenotype-genotype characteristics of SRD5A2 in a large Chinese 5α-RD2 deficiency cohort through multi-centre analysis.

Methods: 190 subjects diagnosed with 5α-RD2 deficiency were consecutively enrolled from eight medical centres in China. Their clinical manifestations and genetic variants were analysed.

Results: Hypospadias (isolated or combined with microphallus and/or cryptorchidism) was fairly common in the enrolled subjects (66.32%). 42 variants, including 13 novel variants, were identified in SRD5A2. Homozygous and compound heterozygous mutations presented in 38.42% and 61.58% of subjects, respectively, and predominated in exons 1, 4 and 5. The most prevalent variant was c.680G > A (52.37%), followed by c.16C > T, (10.79%), c.607G > A, (9.21%) and c.737G > A, (8.95%). However, their distributions were different: c.680G > A was more common in South China than in North China (62.62% vs 39.16%, p < 0.001), whereas the regional prevalence of c.16C > T was reversed (6.07% vs 16.87%, p = 0.001). Furthermore, c.680G > A prevailed in cases with normal meatus (68.75%) or distal hypospadias (66.28%), compared with those with proximal hypospadias (35.54%, p < 0.001). However, cases with proximal hypospadias showed a higher frequency of c.16C > T (20.48%) than those with normal meatus (3.13%) or distal hypospadias (3.49%, p < 0.001).

Conclusions: This study profiled variable phenotypic presentation and wide mutational spectrum of SRD5A2, revealing its distinctive regional distribution in Chinese patients and further shaping the founder effect and genotype-phenotype correlation of SRD5A2.

Keywords: 5α-reductase type 2 deficiency; distribution; founder effect; genotype–phenotype correlation; steroid 5α-reductase 2 gene.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / deficiency*
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
  • Adolescent
  • Asian People / genetics
  • Child
  • Child, Preschool
  • China
  • Cohort Studies
  • Disorder of Sex Development, 46,XY / genetics*
  • Exons / genetics
  • Female
  • Founder Effect
  • Genetic Association Studies
  • Genetic Testing
  • Genotype
  • Humans
  • Hypospadias / genetics*
  • Infant
  • Male
  • Membrane Proteins / genetics*
  • Mutation
  • Phenotype
  • Steroid Metabolism, Inborn Errors / genetics*


  • Membrane Proteins
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • SRD5A2 protein, human

Supplementary concepts

  • Pseudovaginal Perineoscrotal Hypospadias