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.
- 5α-reductase type 2 deficiency
- steroid 5α-reductase 2 gene
- genotype–phenotype correlation
- founder effect
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BG and YS contributed equally.
Contributors BG carried out analysis, interpreted results, and wrote and revised the manuscript. YS and LF collected and reviewed the multi-center data. JW performed the next-generation sequencing and Sanger sequencing and conducted variants annotation. XZ, ZS, XL, YW, LC, XW, RC, YY and F-HL evaluated the clinical features and provided the data. CG and SC conceived, designed and supervised the project and revised the manuscript. All authors approved the final manuscript.
Funding This study was supported by the National Natural Science Foundation of China (Grant No. 81860272), the Major Research Plan of the Provincial Science and Technology Foundation of Guangxi (Grant No. AB16380219), the China Postdoctoral Science Foundation Grant (Grant No. 2018M630993), the Guangxi Natural Science Foundation (Grant No. 2016GXNSFBA380191 and 2018GXNSFAA281067), the Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals (Grant No. XTYB201808), the Public Health Project for Residents in Beijing (Grant No. Z151100003915103), and the National Key Research and Development Program of China (Grant No. 2016YFC0901505).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the Institutional Medical Ethics Review Board of Beijing Children’s Hospital (ID: 2012-28).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information.