MSH4 and MSH5 variants in premature ovarian insufficiency: A literature review and case study

Premature ovarian insufficiency (POI) affects up to 4% of women under 40 years, with genetic factors implicated in a substantial proportion of cases. MSH4 and MSH5 encode components of the MutSγ complex, which stabilises Holliday junctions during meiotic recombination. This review examines the evidence for MSH4 and MSH5 involvement in POI. Biallelic MSH4 variants are well-established causes of POI and non-obstructive azoospermia (NOA), with MSH4 recognised as a high-evidence gene on clinical panels. MSH5 variants have similarly been reported in POI and NOA, though many lack functional validation. Affected individuals predominantly present with secondary amenorrhoea, with emerging evidence for milder phenotypes, including diminished ovarian reserve (DOR). Pathogenic variants are typically loss-of-function and/or disrupt conserved functional domains essential for meiotic recombination, in particular the C-terminal ATPase domain found in both MSH4 and MSH5. We also describe two homozygous MSH5 variants not previously reported in POI, identified in our patient cohort. Given the frequent later onset of POI associated with MSH4/MSH5 variants, there are significant implications for cascade screening, enabling predictive genetic testing in at-risk family members.