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MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency
Swapna Desai1, Michelle Wood-Trageser1, Jelena Matic1
1Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
Objective:
To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, 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 age 40 years and presented with elevated follicle-stimulating hormone 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, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 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 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway.
Conclusions:
We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.
Insights
This study found potentially damaging variants in MCM8 and MCM9 genes in women with primary ovarian insufficiency (POI). These findings highlight the role of DNA damage repair genes in reproductive aging and POI.
Area of Science:
- Genetics
- Reproductive Biology
- Molecular Biology
Background:
- Primary ovarian insufficiency (POI) affects women before age 40, leading to infertility.
- Genetic factors, particularly those involved in DNA damage repair (DDR), are implicated in reproductive aging.
Purpose of the Study:
- To investigate the frequency of variants in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9) genes.
- To assess the role of MCM8, MCM9, and related DNA damage repair (DDR) pathway genes in primary ovarian insufficiency (POI).
Main Methods:
- Sequencing of MCM8, MCM9, and DDR-related genes in participants diagnosed with POI.
- Analysis of nucleotide variants, including heterozygous and homozygous pathogenic variants.
Main Results:
- Potentially damaging heterozygous variants in MCM8 (2%) and MCM9 (5%) were identified in POI participants.
- A novel homozygous variant in MCM9, predicted to cause a premature stop codon, was found.
- Biallelic damaging variants in both MCM8 and MCM9 were observed in one participant.
Conclusions:
- A significant number of potentially damaging and novel variants in MCM8 and MCM9 were identified in individuals with POI.
- These findings suggest a role for MCM8 and MCM9 variants in the etiology of primary ovarian insufficiency.
- Further investigation into the MCM8-MCM9 interactome and DDR pathway is warranted for understanding reproductive aging.
