Lessons from 17β-HSD3 deficiency: Clinical spectrum and complex molecular basis in Chinese patients

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency is rarely reported in Chinese patients with 46, XY disorders of sexual development (DSD). Seven subjects with 17β-HSD3 deficiency were identified from 206 Chinese 46, XY DSD patients using targeted next-generation sequencing (NGS). Serum...

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Published inThe Journal of steroid biochemistry and molecular biology Vol. 225; p. 106191
Main Authors Zhu, Hui, Yao, Haijun, Liu, Xuemeng, Xu, Yue, Liu, Yang, Luo, Qingqiong, Chen, Yan, Shi, Yuanping, Chen, Fuxiang, Zhao, Shuangxia, Song, Huaidong, Han, Bing, Qiao, Jie
Format Journal Article
LanguageEnglish
Published England Elsevier Ltd 01.01.2023
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ISSN0960-0760
1879-1220
1879-1220
DOI10.1016/j.jsbmb.2022.106191

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Summary:17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency is rarely reported in Chinese patients with 46, XY disorders of sexual development (DSD). Seven subjects with 17β-HSD3 deficiency were identified from 206 Chinese 46, XY DSD patients using targeted next-generation sequencing (NGS). Serum AD and T levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In silico and functional studies were performed to evaluate the enzymatic activity impairment of HSD17B3 variants. A minigene assay was performed in an exonic splicing variant. Our results showed that four novel and five reported HSD17B3 variants were identified in 7 unrelated patients. The patients showed cryptic presentation during childhood and classical virilization after puberty with T/AD ratio< 0.4. A heterozygous large deletion from the 5’UTR to exon 1 was identified in a patient with a monoallelic variant of p.N130S. Although predicted to be ‘likely pathogenic’, only p. S232P and p. S160F drastically reduced the enzymatic activity of 17β-HSD3. A previously reported ‘missense’ variant c 0.277 G>A (p. E93K) was revealed to have no impact on enzyme activity but resulted in aberrant splicing of exon 3 and was reclassified as an exonic splicing variant. In our study, one nonsense, one exonic splicing, one deletion, one large deletion and five missense variants were detected in patients with 17β-HSD3 deficiency, expanding the clinical and molecular profile of this disorder. In silico analysis should be cautiously interpreted when the heredity pattern and functional study are inconsistent. •17β-HSD3 deficiency has been rarely reported in Chinese patients.•Postpubertal serum T/AD< 0.4 measured by LC-MS/MS support the diagnosis of 17β-HSD3 deficiency.•Functional study rather than in silico analysis should be performed to illustrate the pathogenicity of variants.
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ISSN:0960-0760
1879-1220
1879-1220
DOI:10.1016/j.jsbmb.2022.106191