MCM8 and MCM9 nucleotide variants in women with primary ovarian insufficiency

OBJECTIVE: To assess the frequency of variants, including biallelic pathogenic variants, in MCM8 and MCM9, other genes related to MCM8/9 and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). DESIGN: MCM8, MCM9 and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants. SETTING: Academic research institution Participants: All were diagnosed with POI prior to the age of 40 and presented with elevated FSH levels. INTERVENTIONS: None Main Outcome Measures: We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging. RESULTS: MCM8 was sequenced in 155 POI participants, while MCM9 was sequenced in 151 participants. Three out of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, while 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551* in MCM9 which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in one participant. Out of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, two individuals carried heterozygous damaging variants in genes associated with either MCM8-MCM9 or DDR pathway Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI, and examined multi-allelic association with variants in DDR and MCM8/MCM9 interactome genes.