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Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development

2023; BioMed Central; Volume: 21; Issue: 1 Linguagem: Inglês

10.1186/s12958-022-01045-7

1477-7827

Khouloud Rjiba, Soumaya Mougou-Zerelli, Imen hadj Hamida, G. Saad, Bochra Khadija, Afef Jelloul, Wafa Slimani, Y. Hasni, Sarra Dimassi, Hela Ben Khelifa, Amira Sallem, Molka Kammoun, Hamza Hadj Abdallah, Moez Gribaa, Joëlle Bignon-Topalovic, Sami Chelly, Hédi Khairi, Mohamed Bibi, M. Kacem, Ali Saâd, Anu Bashamboo, Kenneth McElreavey,

Urological Disorders and Treatments

Forty-six ,XY Differences/Disorders of Sex Development (DSD) are characterized by a broad phenotypic spectrum ranging from typical female to male with undervirilized external genitalia, or more rarely testicular regression with a typical male phenotype. Despite progress in the genetic diagnosis of DSD, most 46,XY DSD cases remain idiopathic.To determine the genetic causes of 46,XY DSD, we studied 165 patients of Tunisian ancestry, who presented a wide range of DSD phenotypes. Karyotyping, candidate gene sequencing, and whole-exome sequencing (WES) were performed.Cytogenetic abnormalities, including a high frequency of sex chromosomal anomalies (85.4%), explained the phenotype in 30.9% (51/165) of the cohort. Sanger sequencing of candidate genes identified a novel pathogenic variant in the SRY gene in a patient with 46,XY gonadal dysgenesis. An exome screen of a sub-group of 44 patients with 46,XY DSD revealed pathogenic or likely pathogenic variants in 38.6% (17/44) of patients.Rare or novel pathogenic variants were identified in the AR, SRD5A2, ZNRF3, SOX8, SOX9 and HHAT genes. Overall our data indicate a genetic diagnosis rate of 41.2% (68/165) in the group of 46,XY DSD.