Premature ovarian failure (POF), also termed primary ovarian insufficiency, is a common disorder in women of reproductive age. This discussion focuses predominately on single genes whose perturbations are associated with POF. Perturbations known to have deleterious effects were initially derived from hypothesis-driven candidate gene interrogations. Genes on the X chromosome considered causative for isolated POF include FMR1, PGRMCI, and BMP15. Genes identified on autosomes include FSHR, GDF9, NR5A1, NOBOX, FIGLA, STAG3, FOXL2, HFM1, SOHLH1, MCM8, MCM9, and MSH5. The most common single nuclear causative gene in syndromic POF is a premutation of FMR1, but other examples of proven syndromic POF include the blepharophimosis-ptosis-epicanthus inversus syndrome due to FOXL2, and proximal symphalangism (SYM1) and multiple synostosis syndrome (SYNS1) due to NOG perturbations. Mitochondrial DNA mutations or nuclear DNA mutations disrupting mitochondrial function can also be causative for syndromic POF, as illustrated by Perrault syndrome (several genes) and progressive external ophthalmoplegia due to DNA polymerase γ. Genome-wide association studies are also revealing regions potentially associated with POF, some of which are plausible, but often without obvious causative genes.
