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Analysis of the molecular parameters that could predict the risk of manifesting premature ovarian failure in female premutation carriers of fragile X syndrome

Tejada, Maria-Isabel PhD1; García-Alegría, Eva BS1; Bilbao, Amaia PhD2; Martínez-Bouzas, Cristina PhD1; Beristain, Elena BS1; Poch, Marisa MD3; Ramos-Arroyo, Maria A. MD4; López, Blanca PhD5; Fernandez Carvajal, Isabel MD, PhD5; Ribate, Maria-Pilar PhD6; Ramos, Feliciano MD6

doi: 10.1097/gme.0b013e3181647762

Objective: To study three molecular parameters (number of CGG repeats, X-inactivation ratio, and expression of FMR1 mRNA) in premutation carriers of fragile X syndrome with and without premature ovarian failure (POF) to find differences between these two groups that could be useful in reproductive counseling.

Design: A retrospective clinical and molecular genetic study of 42 known premutation carriers of fragile X syndrome aged 40 years or older, 25 with POF and 17 without. A blood sample to obtain mRNA was taken from all of them. They all lived in five autonomous communities in northern Spain.

Results: Although the relationship among mRNA levels, X-inactivation ratio, and CGG repeats seems to be similar both in women with POF and in those without: in women with POF, the effect of the CGG repeats on the mRNA levels was statistically significant (P = 0.0437), but in women without POF, it was not (P = 0.0724). Moreover, we confirmed previous results on the nonlinear association between CGG repeat number and the manifestation of POF, showing that the likelihood of having POF was significantly higher with fewer than 100 CGG repeats compared with 100 or more CGG repeats (odds ratio = 13.09, P = 0.0240).

Conclusions: Our present work suggests that mRNA and X-inactivation studies in blood are not relevant in predicting POF in female premutation carriers of fragile X syndrome. However, having a permutation of fewer than 100 repeats could represent a significant risk of POF.

By studying 42 known premutation carriers of fragile X syndrome aged 40 or older, 25 with premature ovarian failure and 17 without, this study found that having a premutation of fewer than 100 repeats could represent a significant risk of premature ovarian failure.

From the 1Molecular Genetics Laboratory, Cruces Hospital, Barakaldo, Bizkaia; 2Basque Foundation for Health Innovation and Research (BIOEF), Sondika, Bizkaia; 3Pediatrics Department, San Millán Hospital, Logroño; 4Genetics Service, Virgen del Camino Hospital, Pamplona; 5Molecular Biology Institute, (IBGM-CSIC), Universidad de Valladolid, Spain; 6Pediatrics Department, Faculty of Medicine, Zaragoza, Spain.

Received October 18, 2007; revised and accepted December 5, 2007.

Funding/support: This work was supported by FIS (ISCIII) grant no. PI02/0812.

Financial disclosure: None reported.

Address correspondence to: María-Isabel Tejada, PhD, Laboratorio de Genética Molecular. Hospital de Cruces, Plaza de Cruces s/n. 48903 Barakaldo (Bizkaia), Spain. E-mail:

©2008The North American Menopause Society