Disorders of sex development (DSD) are a group of clinical conditions with variable presentation and genetic background. Females with or without development of secondary sexual characters and presenting with primary amenorrhea (PA) and a 46, XY karyotype are one of the classified groups in DSD. In this study, we aimed to determine the genetic mutations in 25 females with PA and a 46, XY karyotype to show correlations with their phenotypes. Routine Sanger sequencing with candidate genes like SRY, AR, SRD5A2 and SF1 which are mainly responsible for 46, XY DSD in adolescent females was performed. In a cohort of 25 patients of PA with 46, XY DSD where routine Sanger sequencing failed to detect the mutations, next generation sequencing (NGS) of a targeted gene panel with 81 genes was used for the molecular diagnosis. The targeted sequencing identified total 21 mutations including eight novel variants in 20 out of 25 patients with DSD. The most frequently identified mutations in our series were in AR (36%), followed by SRD5A2 (20%), SF1 (12%), DHX37 (4%), HSD17B3(4%) and DMRT2 (4%). We could not find any mutation in the DSD related genes in five (20%) patients due to complex molecular mechanisms in 46, XY DSD, highlighting the possibility of new DSD genes which are yet to be discovered in these disorders. In conclusion, genetic testing including cytogenetics and molecular genetics is important for the diagnosis and management of 46, XY DSD cases.

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