Premature Ovarian Failure 11

A number sign (#) is used with this entry because of evidence that premature ovarian failure-11 (POF11) is caused by heterozygous mutation in the ERCC6 gene (609413) on chromosome 10q11.

Description

Premature ovarian failure-11 (POF11) is characterized by secondary amenorrhea and hypergonadotropic ovarian insufficiency, with elevated serum follicle-stimulating hormone (FSH; see 136530) levels before age 40 years (Qin et al., 2015).

For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).

Clinical Features

Qin et al. (2015) studied a Han Chinese family in which 4 women over 2 generations experienced secondary amenorrhea. The proband was a 28-year-old woman who experienced secondary amenorrhea at age 23 and had serum FSH levels exceeding 40 IU/L. She had 2 childless paternal aunts who experienced secondary amenorrhea at ages 18 and 27 years, respectively. In addition, a paternal cousin, who was oligomenorrheic after menarche at age 14 and gave birth at age 30, developed amenorrhea at age 37.

Molecular Genetics

In a Han Chinese family in which 4 women over 2 generations experienced secondary amenorrhea, Qin et al. (2015) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the ERCC6 gene (G746D; 609413.0016) that segregated with disease in the family and was not found in the 1000 Genomes or dbSNP (build 134) databases. Analysis of ERCC6 in 432 sporadic POF patients revealed 2 women with heterozygous mutations in ERCC6, a nonsense mutation (E215X; 609413.0017) in 1 and a missense mutation (V1056I) in the other. Neither mutation was found in 400 female controls. Both women experienced normal puberty with regular menses after menarche at 14 and 15 years of age, and experienced secondary amenorrhea at age 24 and 25; neither had achieved pregnancy. Karyotype and FMR1 (309550) premutation analysis were normal in both women.