ANKRD31 – Premature Menopause

The association between ANKRD31 and premature menopause is supported by multiple lines of evidence from both genetic studies and functional assessments. In a large exome sequencing study of 1,030 patients with primary ovarian insufficiency (POI), two pathogenic heterozygous variants in ANKRD31 were identified in a cohort of seven patients (PMID:34257419). This finding, observed alongside pathogenic variants in related meiotic genes, emphasizes that ANKRD31 plays a role in ovarian development via its involvement in meiotic double strand break (DSB) formation.

Genetic evidence indicates that the reported variants affect the gene product in a dosage‐dependent manner. One notable variant is c.1184_1187del (p.Val395fs), which is predicted to result in a frameshift and premature truncation. Although the number of probands is modest, the presence of different variant classes (including splice site changes) across independent patients supports the pathogenicity and clinical relevance of anomalies in ANKRD31 for premature menopause (PMID:34257419).

The mode of inheritance appears to be autosomal dominant as heterozygous variants in ANKRD31 are sufficient to cause a pathogenic effect through haploinsufficiency. This is further corroborated by the functional studies demonstrating that the ANKRD31 variants impair its interaction with the DSB formation partner REC114, thereby disrupting the normal meiosis process (PMID:34257419).

Segregation analysis, although not extensively detailed with additional affected relatives reported, is supported indirectly by the dosage-dependent effect observed and the alignment of phenotypes with the identified heterozygous pathogenic variants.

Experimental evidence from functional assays provides a clear mechanistic link to disease pathogenesis. The impaired molecular interactions seen in vitro under conditions of haploinsufficiency lend strong support to the idea that ANKRD31 malfunction contributes directly to the onset of premature menopause by affecting the generation of primordial follicles through disrupted DSB formation (PMID:34257419).

In summary, the genetic and functional evidence combined offer a robust narrative linking ANKRD31 variants with premature menopause. This association facilitates diagnostic decision‑making and informs both genetic counseling and potential future therapeutic development. Key take‑home: ANKRD31 alterations, even in the heterozygous state, are clinically relevant to premature menopause and warrant further investigation in a diagnostic setting.

References

• Genetics in medicine : official journal of the American College of Medical Genetics • 2021 • Pathogenic variants of meiotic double strand break (DSB) formation genes PRDM9 and ANKRD31 in premature ovarian insufficiency PMID:34257419
• Best practice & research. Clinical endocrinology & metabolism • 2022 • Genetics of ovarian insufficiency and defects of folliculogenesis PMID:34794894
• Proceedings of the National Academy of Sciences of the United States of America • 2023 • In vivo versus in silico assessment of potentially pathogenic missense variants in human reproductive genes PMID:37459509

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