جلسه دفاع از پاياننامه دكتراي ژنتيك پزشكي توسط سركار خانم دكتر آزاده شجاعي در ساعت 13 روز يكشنبه 17 دي ماه در محل گروه ژنتيك برگزار ميگردد. اساتيد راهنما: جناب آقاي دكتر جواد توكلي بزاز- سركار خانم دكتر فرخنده بهجتي استاد مشاور: سركار خانم دكتر مريم رزاقي آذر Abstract Introduction: Disorders of sex development (DSD) belongs to uncommon pathologies and result from abnormalities during gonadal determination and differentiation. Among these disorders, there are especially rare forms such as 46, XY gonadal dysgenesis, which is very heterogeneous in terms of genetic architecture various genes are involved in gonadal determination and differentiations, and their mutations have been associated with gonadal dysgenesis. Among these, SRY, NR5A1, DHH, DAX1 and WNT4 genes, are clearly known to be associated with these disorders. Despite advances in exploration of genetic mechanisms involved in sex disorders such as gonadal dysgenesis, mutation of known genes are responsible for only a few percentages of these disorders. By now, more than 50% of children with severe 46, XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Therefore, there are probably some other potential genes or loci that play an important role in sexual determination and differentiation disorders like gonadal dysgenesis that are awaiting for further analysis. Methods: This study investigates whether chromosomal rearrangements or SRY, NR5A1, DHH, DAX1 and WNT4 genes are implicated in cases of 46, XY gonadal dysgenesis. In addition, it examines whether the routine cytogenetic analysis, sequencing and other molecular techniques of these genes could give some clues to the etiology of these disorders. We recruited patients that were clinically suspicious for 46,XY gonadal dysgenesis of unknown etiology Cytogenetic analysis as well as the direct sequencing of the SRY, NR5A1and DHH gene were performed for all cases. MLPA technique was used to detect deletions and duplications in DAX1 and WNT4 genes and subsequent imbalances were confirmed by real time PCR. Additionally, other potential loci were investigated by whole genome Array CGH method. Results: In this study, one new chromosomal rearrangement and SRY deletion was found in one and five patients, respectively. Previously described NR5A1, DHH and AR allelic variants were observed. One pathogenic c.2522G>A mutation of AR gene was found in two affected brothers. A heterozygous partial deletion was present in NR5A1 gene and heterozygous partial duplication was found in WNT4 gene. These deletions/duplications were subsequently confirmed by real time PCR method. Array CGH results confirmed the chromosomal abnormality in the patient with abnormal chromosome 13, derived from a maternal translocation between chromosome 7 and 13 and showed the exact region of rearrangements. Also, one partial deletion was detected in the SOX2OT gene. Conclusion: Autosomal chromosome abnormalities could also play a role in disorders of sex developments. SRY gene deletion still has a significant role in these disorders and has a similar incidence in our patients compared with other reports and should be the first gene for testing in GD. Del/dup mutations found to be more common than point mutations in our patients. Therefore, it might be preferred to check Del/dup mutations prior to point mutations. SOX2OT might have a potential role in gonadal dysgenesis and it should be taken into account in molecular approaches to study GD patients. Array CGH is a valuable tool for finding responsible genes in GD and could unravel some potential loci in this regard.