期刊
JOURNAL OF THE ENDOCRINE SOCIETY
卷 3, 期 12, 页码 2341-2360出版社
ENDOCRINE SOC
DOI: 10.1210/js.2019-00306
关键词
desert hedgehog; DSD; DHX37; sex determination; SRY; steroidogenic factor-1
资金
- Wellcome Trust [098513/Z/12/Z, 209328/Z/17/Z]
- Great Ormond Street Hospital Children's Charity [V2518]
- National Institute for Health Research, Great Ormond Street Hospital Biomedical Research Centre [IS-BRC-1215-20012]
- MRC/Wellcome Trust [MR/R006237/1]
- National Laboratory for High Performance Computing (NLHPC) [ECM-02]
- Wellcome Trust [098513/Z/12/Z] Funding Source: Wellcome Trust
- National Institutes of Health Research (NIHR) [IS-BRC-1215-20012] Funding Source: National Institutes of Health Research (NIHR)
Context: The genetic basis of human sex development is slowly being elucidated, and >40 different genetic causes of differences (or disorders) of sex development (DSDs) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available. Objective: We used a targeted next-generation sequencing approach to analyze known and candidate genes for DSDs in individuals with no specific molecular diagnosis. Participants and Design: We studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17 beta-hydroxysteroid dehydrogenase deficiency type 3, 5a-reductase deficiency type 2, and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis and those with a broad partial androgen insensitivity syndrome label. Targeted sequencing of 180 genes was undertaken. Results: Overall, a likely genetic cause was found in 16 of 52 (30.8%) individuals (22.2% CGD, 40.0% pvDSD). Pathogenic variants were found in sex-determining region Y (SRY; n = 3), doublesex and mab3-related transcription factor 1 (DMRT1; n = 1), NR5A1/steroidogenic factor-1 (SF-1) (n = 1), and desert hedgehog (DHH; n = 1) in the CGD group, and in NR5A1 (n = 5), DHH (n = 1), and DEAH-box helicase 37 (DHX37; n = 4) in the pvDSD group. Conclusions: Reaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible.
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