ESPE Abstracts

Background: Ovarian Dysgenesis (OD) is a rare genetically heterogeneous XX Disorder of Sex Development. It presents clinically with primary amenorrhea, hypergonadotrophic hypogonadism and infertility. The genetic basis of OD remains unknown in 70% of cases. To identify novel genetic causes of OD, we are investigating families with one or more patients diagnosed with OD.

Methods: Using a patient-based approach, WES was performed in 26 families with one or more patients diagnosed with OD. In each family, candidate variants were identified using filtering criteria, tested for segregation, and evaluated using various molecular assays customized to the specific candidate gene. Chromosomal breakage analysis was performed on patient-derived lymphocytes using Mitomycin C (MMC).

Results: Out of 26 families we identified the genetic cause in 18 families (69%) including variants in 12 candidate novel genes (46%) such as FIGNL1, MCM10, TALDO1, SYNE3, ZP3 and more. Among them 4 are DNA damage response (DDR) genes (33%). Overall, variants in DDR genes including FIGNL1, MCM10, STAG3, FAN1 and SWI5 were causing 28% of the identified cases. Chromosomal breakage analysis on patient derived cells induced by 300mM MMC showed chromosomal instability in patients with variants in DDR genes: 5.00±0.59 vs 2.1±0.34 breaks/cell (P = 0.0003) for FIGNL1, 3.08±0.36 vs 1.90±0.27 breaks/cell (P = 0.009) for MCM10, 4.00±0.47 vs 1.90±0.29 breaks/cell (P = 0.0005) for FAN1 and 2.77±0.28 vs 1.77±0.23 breaks/cell (P = 0.017) for SWI5, while no instability has been identified on patients with no DDR gene involvement. Two of the families with variants in DDR also demonstrated cancer predisposition, including breast and ovarian cancer (MCM10 and FIGNL1).

Conclusion: Clinic-to-bench approach is a powerful tool for identifying new genes and pathways involved in OD. Due to the high incidence (33%) of DDR genes variants in the etiology and pathogenesis of OD, it seems justified to include chromosomal breakage analysis as a part of the initial diagnosis in such patients. The results can direct and guide to the genetic cause and to further clinical evaluation and treatment of patients and their family members. Furthermore, a positive result does indicate both a thorough investigation of the family pedigree highlighting cancer cases and periodic surveillance in affected patients and their family members for prevention and early diagnosis of malignant diseases.