Gomes Nathalia Lisboa, Batista Rafael Loch, Nishi Mirian Y, Lerário Antônio Marcondes, Silva Thatiana E, de Moraes Narcizo Amanda, Benedetti Anna Flávia Figueredo, de Assis Funari Mariana Ferreira, Faria Junior José Antônio, Moraes Daniela Rodrigues, Quintão Lia Mesquita Lousada, Montenegro Luciana Ribeiro, Ferrari Maria Teresa Martins, Jorge Alexander A, Arnhold Ivo J P, Costa Elaine Maria Frade, Domenice Sorahia, Mendonca Berenice Bilharinho
Unidade de Endocrinologia do Desenvolvimento/ LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Unidade de Adrenal, Serviço de Endocrinologia, Santa Casa de Belo Horizonte, Belo Horizonte, Brazil.
J Clin Endocrinol Metab. 2022 Apr 19;107(5):e1797-e1806. doi: 10.1210/clinem/dgac064.
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).
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.
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.
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.
大规模平行测序（MPS）技术已成为诊断多种儿科遗传综合征的一线方法。然而，在诊断46,XY性发育异常（DSD）时，MPS尚未与临床/生化数据一起系统地整合到诊断流程中。
分析单独的表型分类或与基因评估（主要是MPS）相结合对一大群46,XY DSD患者诊断的贡献。
设计/患者：纳入了来自巴西DSD中心的209例非综合征性46,XY DSD索引病例。患者最初根据临床和生化数据分为3个亚组：性腺发育不全（GD）、雄激素分泌/作用障碍和病因不明的DSD。通过桑格测序和/或MPS进行分子遗传学研究。
68.4%的索引病例通过临床/生化分类为GD或激素分泌/作用障碍。其中，分别有36%和96.5%获得了分子诊断。对于其余31.6%分类为临床病因不明的DSD患者，31.8%获得了分子诊断。总体而言，该队列中有59.3%获得了分子诊断。临床/生化和分子方法相结合诊断了78.9%的患者。除1例病例外，临床/生化分类与基因诊断均相符。DHX37和NR5A1变异分别是GD和临床病因不明的DSD患者中最常见的遗传原因。
临床/生化与基因方法相结合显著改善了46,XY DSD的诊断。作为诊断46,XY DSD的一线方法，MPS可能会降低诊断检查工作的复杂性。
