Genetic Screening of Iranian Patients with 46,XY Disorders of Sex Development.

Background: Disorders of sex development (DSDs) belong to uncommon pathologies and result from abnormalities during gonadal determination and differentiation. Various gene mutations involved in gonadal determination and differentiation have been associated with gonadal dysgenesis. Despite advances in exploration of genes and mechanisms involved in sex disorders, most children with severe 46,XY DSDs have no definitive etiological diagnoses; therefore, the possibility that other genes or loci might play important roles in these disorders needs to be explored.

Methods: Patients (37) clinically suspicious for 46,XY gonadal dysgenesis (46,XY GD) of unknown etiology were studied. , encoding the sex-determining region Y protein, , encoding a transcription factor called steroidogenic factor 1, and , encoding the desert hedgehog protein, were directly sequenced. Multiplex ligation-dependent probe amplification (MLPA) was used to detect deletions in , encoding the DAX1 protein, and , encoding the WNT4 protein, and real-time PCR (qPCR) confirmed the MLPA data. Other potential loci have been investigated in the complete genome using Array-Comparative Genomic Hybridization, (Array CGH).

Results: The deletion was found in five patients. One each of previously described , and (androgen receptor) allelic variants were identified. A pathogenic c.2522G>A mutation was found in two affected brothers. A heterozygous partial deletion was found in and heterozygous partial duplications were found in . These deletions and duplications (del/dup) were confirmed by qPCR. The Array CGH result demonstrated one partial deletion in , which encodes a member of the SOX family of transcription factors, and the exact region of the rearrangements.

Conclusion: According to our study, del/dup mutations could be checked prior to point mutations, SOX2-OT has a potential role in gonadal dysgenesis, and Array CGH has a prominent role in gonadal dysgenesis diagnosis.