期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 107, 期 5, 页码 E1797-E1806出版社
ENDOCRINE SOC
DOI: 10.1210/clinem/dgac064
关键词
differences in sex development; 46; XY gonadal dysgenesis; massively parallel sequencing; DHX37
资金
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [305743/2011-2]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [05/04726-0, 07/512156, 10/51102-0, 2013/02162-8, 2014/50137-5]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES/PNPD)
The combination of clinical/biochemical and genetic approaches significantly improves the diagnosis of 46,XY DSD, and MPS as a first-line approach helps simplify the diagnostic workflow.
Context Massively parallel sequencing (MPS) technologies have emerged as a first-tier approach for diagnosing several pediatric genetic syndromes. However, MPS has not been systematically integrated into the diagnostic workflow along with clinical/biochemical data for diagnosing 46,XY differences of sex development (DSD). Objective To analyze the contribution of phenotypic classification either alone or in association with genetic evaluations, mainly MPS, for diagnosing a large cohort of 46,XY DSD patients. Design/patients 209 nonsyndromic 46,XY DSD index cases from a Brazilian DSD center were included. Patients were initially classified into 3 subgroups according to clinical and biochemical data: gonadal dysgenesis (GD), disorders of androgen secretion/action, and DSD of unknown etiology. Molecular genetic studies were performed by Sanger sequencing and/or MPS. Results Clinical/biochemical classification into either GD or disorders of hormone secretion/action was obtained in 68.4% of the index cases. Among these, a molecular diagnosis was obtained in 36% and 96.5%, respectively. For the remainder 31.6% classified as DSD of clinically unknown etiology, a molecular diagnosis was achieved in 31.8%. Overall, the molecular diagnosis was achieved in 59.3% of the cohort. The combination of clinical/biochemical and molecular approaches diagnosed 78.9% of the patients. Clinical/biochemical classification matched with the genetic diagnosis in all except 1 case. DHX37 and NR5A1 variants were the most frequent genetic causes among patients with GD and DSD of clinical unknown etiology, respectively. Conclusions The combination of clinical/biochemical with genetic approaches significantly improved the diagnosis of 46,XY DSD. MPS potentially decreases the complexity of the diagnostic workup as a first-line approach for diagnosing 46,XY DSD.
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