Gamete Quality & DNA Repair

Intronic variant in TLK1 (tousled like kinase 1), a DNA-damage-repair and chromatin-assembly kinase; each copy of the T allele may be associated with earlier age at natural menopause by approximately 10 weeks, suggesting a modest influence on ovarian reserve and reproductive lifespan

Intronic variant in TP63 (p63), the master DNA-damage checkpoint gene in primordial follicle oocytes; the T allele is associated with later age at natural menopause, reflecting better oocyte quality control and preservation of the ovarian reserve over time

Rare intronic variant in a lncRNA antisense to KIF2B (chromosome 17q22), identified in the Ruth et al. 2021 Nature GWAS as associated with age at natural menopause; KIF2B encodes a kinesin-13 microtubule depolymerase essential for bipolar spindle assembly during oocyte meiosis

An intronic variant in HELQ (helicase, POLQ-like) on chromosome 4q21.23; the A allele is associated with delayed age at natural menopause (+0.238 years/allele, p=6×10⁻¹⁷²), reflecting HELQ's role in maintaining the oocyte DNA-repair capacity that preserves ovarian reserve across the reproductive lifespan

Intronic variant in EXO1 (exonuclease 1), a DNA mismatch repair and meiotic recombination enzyme; each copy of the C allele is associated with approximately 10 fewer weeks before natural menopause onset, implicating impaired oocyte DNA repair in accelerated follicle depletion

Missense variant in the MLH1 ATPase domain (c.655A>G, p.Ile219Val) that substitutes isoleucine for valine at a conserved hydrophobic position; classified benign for Lynch syndrome with intact mismatch repair activity, but the G allele shows modest associations with altered DNA repair kinetics and may influence meiotic recombination efficiency

Missense variant in MRE11 (p.Met698Val, T>C on plus strand) at a poorly conserved position outside known nuclease or RAD50-interaction domains; classified benign by multiple ClinVar submitters, but MRE11 is a core component of the MRN complex (MRE11-RAD50-NBS1) that initiates homologous recombination repair of DNA double-strand breaks — including in meiotic cells, where MRN is required for crossover formation and spermatogenic integrity

Triallelic missense variant in the P-glycoprotein efflux pump that reduces the transporter's ability to expel xenobiotics — including environmental toxicants such as pesticides, heavy metals, and endocrine disruptors — from gamete-forming cells, potentially increasing DNA damage susceptibility in oocytes and spermatocytes

Intronic variant in XPO4 (chromosome 13q12.11) at a locus associated with age at natural menopause in the large-scale Ruth et al. 2021 GWAS; XPO4 encodes a nuclear export receptor required for cytoplasmic delivery of ribosomal subunits and regulatory factors, a process critical for oocyte translational competence and mitochondrial ribosome maintenance

Missense variant in PRIM1 (DNA primase small subunit) that changes aspartate to alanine at position 5 of the protein; the G allele (Asp5Ala) is associated with later age at natural menopause by approximately 0.35 years per copy, implicating DNA replication priming fidelity in the rate of ovarian follicle depletion

Splice-region variant in MSH2 (c.2006-6T>C) located 6 bases upstream of exon 13 in the mismatch repair gene; the C allele is associated with altered mismatch repair expression and modestly elevated cancer prognosis signals across multiple tumour types; classified benign for Lynch syndrome

Missense variant in LTBP4 encoding Val194Ile; the A allele (Ile) forms the IAAM haplotype that binds latent TGF-β1 with higher avidity, reducing free TGF-β signaling and acting as a protective modifier of Duchenne muscular dystrophy severity — IAAM homozygotes retain ambulation approximately 1.8 years longer than VTTT carriers under glucocorticoid treatment

Intronic variant in HSPA4L within a chromosome 4 haplotype spanning PLK4; the A allele is associated with increased mitotic-origin embryo aneuploidy, reduced blastocyst formation in IVF, and elevated early recurrent miscarriage risk in women; HSPA4L itself is highly expressed in spermatogenic cells and required for normal sperm production

Intronic variant in POLG (mitochondrial DNA polymerase gamma) on chromosome 15q26.1; the G allele is associated with earlier natural menopause by approximately 9–10 weeks per allele, implicated through mitochondrial DNA replication fidelity and oocyte energy metabolism

Intronic variant in MCM8 (minichromosome maintenance 8 helicase) on chromosome 20p12.3; each A allele is associated with approximately 0.5 years of delayed age at natural menopause, suggesting that reduced MCM8-mediated DNA repair activity modestly accelerates ovarian follicle depletion in people carrying the common T allele

Intronic variant in ZNF346 (chromosome 5q35.2), a proxy SNP for the UIMC1/RAP80 DNA-repair locus; the G allele may be associated with earlier age at natural menopause and modestly increased susceptibility to primary ovarian insufficiency

An intronic variant in UIMC1 (RAP80), the core ubiquitin-binding subunit of the BRCA1-A complex that recruits BRCA1 to DNA double-strand breaks; the T allele is associated with earlier age at natural menopause, implicating reduced DNA repair fidelity in accelerated ovarian ageing

A 3'UTR regulatory variant in HEY2, a Notch signaling transcription factor expressed in pregranulosa cells during the critical neonatal window of primordial follicle assembly; the T allele is derived and globally common, and may tag elevated HEY2 expression relative to the G reference; GG homozygotes represent the baseline HEY2 signaling state.

Missense variant in the MSH2 connector domain (c.965G>A, p.Gly322Asp) that substitutes glycine for aspartate at a conserved structural position; classified benign for Lynch syndrome, but carriers transmit significantly more germline microsatellite de novo mutations to offspring, reflecting subtly reduced mismatch repair fidelity in germ cells

Intronic regulatory variant in EXO1 (exonuclease 1) that increases EXO1 enhancer activity; the G allele is associated with earlier age at natural menopause (ovarian ageing) and elevated breast cancer risk through upregulated EXO1 expression

An intronic PCOS susceptibility variant in MAPRE1 (chromosome 20q11.21) identified in the Day 2018 European GWAS meta-analysis; the T allele tags a haplotype associated with altered MAPRE1 expression, with mechanistic links to spindle instability and chromosome missegregation during oocyte meiosis

A 3'UTR variant in INO80 that is associated with delayed ovarian ageing; the T allele tags a haplotype linked to greater INO80 chromatin remodeling activity, supporting DNA double-strand break repair and telomere maintenance in oocytes.