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- Title
Contribution of Clinical and Genetic Approaches for Diagnosing 209 Index Cases With 46,XY Differences of Sex Development.
- Authors
Lisboa Gomes, Nathalia; Loch Batista, Rafael; Nishi, Mirian Y.; Marcondes Lerário, Antônio; Silva, Thatiana E.; de Moraes Narcizo, Amanda; Figueredo Benedetti, Anna Flávia; de Assis Funari, Mariana Ferreira; Faria Junior, José Antônio; Rodrigues Moraes, Daniela; Lousada Quintão, Lia Mesquita; Ribeiro Montenegro, Luciana; Martins Ferrari, Maria Teresa; Jorge, Alexander A.; Arnhold, Ivo J. P.; Frade Costa, Elaine Maria; Domenice, Sorahia; Bilharinho Mendonca, Berenice
- Abstract
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.
- Subjects
SEX differentiation disorders; GONADAL dysgenesis
- Publication
Journal of Clinical Endocrinology & Metabolism, 2022, Vol 107, Issue 5, pe1797
- ISSN
0021-972X
- Publication type
Article
- DOI
10.1210/clinem/dgac064