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

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

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

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 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

Missense variant in the MSH2 lever 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