Analysis of FMR1 gene premutation and X chromosome cytogenetic abnormalities in 100 Tunisian patients presenting premature ovarian failure.

OBJECTIVE: To evaluate the prevalence of FMR1 premutations and X chromosome cytogenetic abnormalities in a large cohort of Tunisian women with premature ovarian failure (POF). PATIENTS AND METHODS: The cohort consisted of 127 Tunisian women with POF referred by endocrinologists and gynecologists for genetic investigation in the context of idiopathic POF and altered hormonal profiles. Clinical information concerning the reproductive function in the family, previous hormonal measurements and/or possible fertility treatment were collected. Karyotype, FISH analyses, FMR1 and FMR2 testing were performed for all patients. RESULTS: Fifteen patients (11.81%) presented structural or numerical X chromosomal abnormalities. Moreover, we detected in 12 patients (10.71%) a high level of X mosaicism. Analysis of FMR1 gene in the 100 patients without X chromosomal abnormalities showed that five percent of the patients carried a FMR1 premutation allele. On the other hand, the FMR2 screening did not reveal any deletion. CONCLUSION: Our study confirms the major role of X chromosome abnormalities in POF and highlights the importance of karyotype analyses and FMR1 screening. These investigations provide valuable information for diagnosis and genetic counseling for these women who still have a 5% chance of spontaneous conception.

Mutational screening of SF1 and WNT4 in Tunisian women with premature ovarian failure.

BACKGROUND: WNT4 and SF1 genes play an important role in ovarian development. They constitute coherent candidate genes associated with premature ovarian failure (POF) pathogenesis. METHODS: We sequenced the coding region of WNT4 and SF1 in 55 Tunisian women with POF and 100 healthy controls. RESULTS: We identified a synonymous variation in WNT4 (c.99G>A, p.Ser33Ser) and a substitution (c.G437C) in SF1 gene inducing G146 to Ala (GGG-GCG) missense mutation. WNT4 (c.99G>A, p.Ser33Ser) was not associated with POF pathology. However, a positive association of SF1 Gly146Ala polymorphism was noted. Gly146Ala minor allele frequency was significantly higher (p=0.029) in POF patients versus controls and Ala allele containing genotypes (p=0.005) were positively associated with POF pathology. The carriage of 146Ala allele was also associated with a significant reduction in estradiol plasma levels. CONCLUSIONS: SF1 Gly146Ala polymorphism seems to be associated with POF pathology in the Tunisian population likely by reducing estradiol levels.