Exploring the clinical implications of novel SRD5A2 variants in 46,XY disorders of sex development.

Yu MAO; Jian-Mei HUANG; Yu-Wei CHEN-ZHANG; He LIN; Yu-Huan ZHANG; Ji-Yang JIANG; Xue-Mei WU; Ling LIAO; Yun-Man TANG; Ji-Yun YANG

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Exploring the clinical implications of novel SRD5A2 variants in 46,XY disorders of sex development.

Author: Yu MAO ¹ ; Jian-Mei HUANG ² ; Yu-Wei CHEN-ZHANG ³ ; He LIN ³ ; Yu-Huan ZHANG ³ ; Ji-Yang JIANG ³ ; Xue-Mei WU ³ ; Ling LIAO ³ ; Yun-Man TANG ¹ ; Ji-Yun YANG ³
Author Information

1. Department of Pediatric Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
2. Medical Genetics Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou 450003, China.
3. The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Centre for Medical Genetics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
Publication Type:Journal Article
MeSH: Humans; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics*; Disorder of Sex Development, 46,XY/blood*; Male; Membrane Proteins/genetics*; Child, Preschool; Child; Retrospective Studies; Adolescent; Female; Mutation; Testosterone/blood*; Infant; Dihydrotestosterone/blood*
From: Asian Journal of Andrology 2025;27(2):211-218
CountryChina
Language:English
Abstract: This study was conducted retrospectively on a cohort of 68 patients with steroid 5 α-reductase 2 (SRD5A2) deficiency and 46,XY disorders of sex development (DSD). Whole-exon sequencing revealed 28 variants of SRD5A2 , and further analysis identified seven novel mutants. The preponderance of variants was observed in exon 1 and exon 4, specifically within the nicotinamide adenine dinucleotide phosphate (NADPH)-binding region. Among the entire cohort, 53 patients underwent initial surgery at Sichuan Provincial People's Hospital (Chengdu, China). The external genitalia scores (EGS) of these participants varied from 2.0 to 11.0, with a mean of 6.8 (standard deviation [s.d.]: 2.5). Thirty patients consented to hormone testing. Their average testosterone-to-dihydrotestosterone (T/DHT) ratio was 49.3 (s.d.: 23.4). Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome; and their T/DHT ratios were below the diagnostic threshold. Furthermore, assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants. These mechanisms include interference with NADPH binding (c.356G>C, c.365A>G, c.492C>G, and c.662T>G) and destabilization of the protein structure (c.727C>T). The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts. Seven novel variations were identified, and the variant database for the SRD5A2 gene was expanded. These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.