Imprinting effect in premature ovarian failure confined to paternally inherited fragile X premutations

Fragile X premutations are considered to be a risk factor for premature ova rian failure (POF), which is usually defined as menopause at age <40 years. Since premutations may be inherited from either the mother or the father, we evaluated the influence of the inheritance pattern on the duration of re productive life in female carriers. The occurrence of POF and age at menopa use in women with a paternally inherited fragile X premutation (PIP) were c ompared to those in women with a maternally inherited fragile X premutation (MIP). We identified 148 women in whom the parental origin of the premutat ion could be determined. In 109 of these women we were able to establish wh ether POF had occurred: 82 women had a PIP, and 27 had a MIP Twenty-three o f the women (28%) with a PIP had POF, versus only 1 (3.7%) with a MIP (two -tailed Fisher's exact test; P = .007). Kaplan-Meier analysis of all 148 pr emutations showed that the age at menopause was significantly lower in the women with a PIP than in the woman with a MIP (Breslow test in Kaplan-Meier analysis; P = .003). Our data strongly suggest that, when POF occurs in fr agile X premutation carriers, a considerable proportion of the premutations are inherited paternally (parent-of-origin effect). We hypothesize that th is map be owing to a paternal genomic imprinting effect.