ESPE2022 Poster Category 1 Sex Differentiation, Gonads and Gynaecology, and Sex Endocrinology (56 abstracts)
Background: Severe XX-DSD and ovarian dysgenesis (OD) are the extreme clinical phenotype of approximately 1% of women that are affected by primary ovarian insufficiency (POI). BMP15 and GDF9 are two members of transforming growth factor ß (TGF-β) superfamily; they share an oocyte-specific expression pattern and play a crucial role in early folliculogenesis. Only XX cases of mutations in BMP15 have been proved to cause human disease. Here we describe a novel homozygous BMP15 mutation in 2 sisters from a consanguineous family presenting with primary amenorrhea.
Clinical Data: The 2 Palestinian sisters, presented with absence of spontaneous puberty, primary amenorrhea and hypergonadotropic hypogonadism (LH: 47 & 31.2, FSH: 130 & 31.2 respectively), Karyotype was 46, XX and pelvic MRI detected a small uterus but no ovaries in both affected sisters.
Molecular Data: next generation sequencing revealed a novel c.G959A:p.C320Y mutation in the BMP15 gene, both parents were heterozygous and two other sisters are prepubertal. As the Cysteine 320 is a highly conserved residue among species (8.006 in PhyloP100, 5.4 in GERP) the mutation is highly predicted to cause protein dysfunction (Revel, Polyphen, Sift) especially as it probably causes structural damage due to lack of cysteine S-S bond in an S-S bonds cluster at BMP15 mature protein chain.
Conclusion: The novel C320Y BMP15 mutation causes ovarian dysgenesis and primary amenorrhea in 2 sisters. The predicted change in S-S bonds may compromise protein function which is currently studied. To our knowledge, this is the first description of this disease in a Palestinian family with molecular confirmation, allowing accurate genetic counseling, early diagnosis of affected kindreds & early therapeutic interventions. Paving the way for genetic testing of primary ovarian insufficiency cases in Palestine.
15 Sep 2022 - 17 Sep 2022