ATP1A4 – Pelvic Organ Prolapse

ATP1A4 has emerged as a candidate gene associated with pelvic organ prolapse based on recent whole exome sequencing studies in young women with pelvic floor dysfunction (PMID:39833541). The study screened a cohort of ten affected individuals with a family history of pelvic floor disorders, and among several ion channel genes, ATP1A4 was highlighted as harboring potentially pathogenic nonsense variants. Although the cohort size is modest, these findings prompt further investigation into the role of ATP1A4 in contributing to pelvic muscle dysfunction.

The overall clinical validity of the ATP1A4–pelvic organ prolapse association is judged as Limited by ClinGen criteria. This rating is based on the small number of probands and the absence of extensive segregation data or independent replication (PMID:39833541). In this study, while several candidate ion channel genes were implicated, ATP1A4-specific variant details were not provided in the mutation list.

Genetic evidence supporting this association is derived from a candidate gene analysis in which family-based whole exome sequencing identified nonsense variants in ATP1A4 among other ion channel genes. The inheritance is presumed to be autosomal recessive given the familial context, yet detailed segregation data and explicit ATP1A4 variant reporting (e.g., an HGVS string) are lacking. Consequently, the genetic evidence is assessed as Limited.

Functional studies mentioned in the report support a role for ion channel dysfunction in pelvic muscle pathology. Although functional assays broadly indicate impaired electrical activity and aberrant muscle contraction consistent with the pelvic organ prolapse phenotype, ATP1A4-specific functional data remain sparse. This contributes to a Limited functional evidence rating.

There is no substantial conflicting evidence regarding the ATP1A4 association; however, the candidate gene approach and the limited cohort necessitate cautious interpretation pending further validation. Additional independent studies with larger cohorts and focused ATP1A4 analyses are required to definitively establish causality.

In summary, while ATP1A4 represents a promising candidate in the genetic architecture of pelvic organ prolapse, current evidence remains preliminary. Future targeted studies, including segregation analyses and ATP1A4-specific functional assays, will be essential to bolster this association.

Key Take‑home: ATP1A4 holds potential as a screening target for familial pelvic organ prolapse, but further validation is required before it can be routinely used in diagnostic decision‑making or commercial applications.

References

• International urogynecology journal • 2025 • Whole Exome Sequencing Reveals Candidate Variants in Ion Channel Genes for Pelvic Muscle Dysfunction in Young Females with a Family History PMID:39833541

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