Premature ovarian failure is clearly a heterogeneous disorder. The terms 'hypergonadotropic ovarian failure' and 'hypergonadotropic ovarian dysgenesis' (see ODG1, 233300) have been used to indicate a group of disorders in which amenorrhea associated with elevated levels of serum gonadotropins occurs long before the age of 40 years (Coulam, 1982). Cytogenetic studies of X-chromosome aberrations have suggested that it is mainly the long arm of the X chromosome that is involved in defects of ovulation (Bione et al., 1998).
Reviews
Qin et al. (2015) reviewed the genetics of primary ovarian insufficiency (POI), also known as POF. They noted that causative genes had been identified in only 20 to 25% of POI cases.
Rossetti et al. (2017) reviewed the genetics of primary ovarian insufficiency, noting that the significance of this disorder was increasing because of the increasing number of women desiring conception beyond 30 years of age, at which point POF prevalence is more than 1%.
Genetic Heterogeneity of Premature Ovarian Failure
Mutations in genes identified within a region defined as POF2 (Xq13.3-q21.1) have been found to cause other forms of POF: POF2A (300511) by mutation in the DIAPH2 gene (300108) and POF2B (300604) by mutation in the POF1B gene (300603). See also POF3 (608996), caused by mutation in the FOXL2 gene (605597) on chromosome 3q22; POF4 (see 300510), caused by mutation in the BMP15 gene (300247) on chromosome Xp11; POF5 (611548), caused by mutation in the NOBOX gene (610934) on chromosome 7q35; POF6 (612310), caused by mutation in the FIGLA gene (608697) on chromosome 2p13; POF7 (612964), caused by mutation in the NR5A1 gene (184757) on chromosome 9q33; POF8 (615723), caused by mutation in the STAG3 gene (608489) on chromosome 7q22; POF9 (615724), caused by mutation in the HFM1 gene (615684) on chromosome 1p22; POF10 (612885), caused by mutation in the MCM8 gene (608187) on chromosome 20p12; POF11 (616946), caused by mutation in the ERCC6 gene (609413) on chromosome 10q11; POF12 (616947), caused by mutation in the SYCE1 gene (611486) on chromosome 10q26; POF13 (617442), caused by mutation in the MSH5 gene (603382) on chromosome 6p21; POF14 (618014), caused by mutation in the GDF9 gene (601918) on chromosome 5q31; POF15 (618096), caused by mutation in the FANCM gene (609644) on chromosome 14q21; POF16 (618723), caused by mutation in the BNC1 gene (601930) on chromosome 15q25; POF17 (619146), caused by mutation in the XRCC2 gene (600375) on chromosome 7q36; POF18 (619203), caused by mutation in the C14ORF39 gene (617307) on chromosome 14q23; POF19 (619245), caused by mutation in the HSF2BP gene (604554) on chromosome 21q22; POF20 (609938), caused by mutation in the MSH4 gene (602105) on chromosome 1p31; POF21 (620311), caused by mutation in the TP63 gene (603273) on chromosome 3q28; POF22 (620548), caused by mutation in KASH5 gene (618125) on chromosome 19q13; and POF23 (620686), caused by mutation in the MEIOB gene (617670) on chromosome 16p13.
In 100 patients with primary or secondary amenorrhea before the age of 40 years, who also exhibited elevated FSH, Bouilly et al. (2016) screened for variants in 19 POF-associated or candidate genes. The authors noted that 8 of the 19 mutation-positive patients carried a genetic defect in more than 1 gene, and that patients with 2 or more variants tended to have a younger age of onset and were more likely have primary rather than secondary amenorrhea. Bouilly et al. (2016) suggested that digenicity and possibly oligogenicity may contribute to POF, noting that this might account for the phenotypic variability and incomplete penetrance that have been observed in patients with POF. [from
OMIM]