FMR1 CGG Repeats In Primary Ovarian Insufficiency Women vs. 2 Comparison Groups


University of Virginia

Principal Investigator

Dr. Steven Young, Obstetrics and Gynecology

Project Run Dates

9/15/2011 to 6/30/2014



Primary Ovarian Insufficiency (POI) is a spectrum of disorders of early ovarian aging characterized by elevated follicle stimulating hormone (FSH) levels ranging from Diminished Ovarian Reserve (DOR, FSH >10 mIU/mL and regular menses) to premature ovarian failure (POF, FSH >40 mIU/mL and amenorrhea before age 40). The Genetics Committee of the American College of Obstetricians and Gynecologists and the American College for Medical Genetics (ACMG) have recommended genetic counseling and fragile X premutation (defined as ~55 - 200 CGG repeats in the FMR1 gene) screening for women with POI. While it is known that 5% of women with POF have a fragile X premutation, little is known about the CGG repeat count in women with DOR. Our preliminary data in 65 women with DOR and one published report (Streuli et al) in 27 women with POI (POF excluded) suggest that CGG repeats of 35-44 are markedly over-represented in women with this phenotype (14-17% prevalence). Current clinical guidelines state that an FMR1 CGG repeat count <45 is not associated with an abnormal phenotype;however our data and that from Streuli suggest that this is incorrect, and that indeed there is an infertility phenotype associated with 35-44 triplet repeats. The proposed study, in direct response to the NIH Research Plan on Fragile X Syndrome and Associated Disorders Objectives 1.4 and 3.1, seeks to substantiate the association between the FMR1 triplet repeat count and this infertility phenotype. This study will compare the CGG repeat count in a cohort of 110 DOR cases with 2 comparison cohorts (680 women with proven fertility and normal ovarian aging defined by natural menopause over age 45 participating in the Study of Women's Health Across the Nation (SWAN), and 170 women who are infertile due to an anatomical reason such as tubal occlusion). DNA samples from the SWAN cohort have already been collected. The second comparison group will be recruited through this grant.