ESPE Abstracts

Background: Diseases of sex development (DSD) are rare heterogeneous disorders ranging from infertility (an estimated 15% of couples worldwide have difficulty conceiving), to severe cases including ambiguous genitalia, sex reversal, and gonadal dysgenesis. The genetic basis of DSD remains unknown in 50% of the severe cases. To identify novel genetic causes of DSD, we are investigating patients in which known causative genes have been excluded. Identifying new genes will help elucidate pathways involved in gonadal development and may allow new interventions for infertility.

Methods: Using a patient-based approach, WES was performed in families with patients diagnosed with DSD. In each family, candidate variants were identified, tested for segregation and evaluated using various molecular assays customized to the specific candidate gene.

Results: We identified three novel genes previously unknown to affect gonadal development in humans. Compound heterozygous frameshift mutations in FIGNL1 cause genomic instability and aberrant chromosomal structures in somatic cells in addition to lack of DNA damage response and cancer predisposition, eventually results in ovarian dysgenesis (OD). A homozygous MCM10 missense mutation demonstrated decreased replication fork rates, resulting in genomic instability and OD. A homozygous TALDO1 missense mutation in the enzymatic catalytic site resulted in reactive oxygen species accumulation and male gonadal dysgenesis.

Conclusions: Identification of the genetic basis for DSD enables relevant treatment and reproductive options. Our studies demonstrate that the clinic-to-bench approach is a powerful tool for identifying new genes and pathways involved in DSD. Moreover, DNA damage response elements are crucial for ovarian development with cancer predisposition implications. Understanding the full cascade and networks of gonadal development, will eventually lead to the development of new therapies for infertility.