CHRM5 – Cauda Equina Syndrome with Neurogenic Bladder

This summary evaluates the association between CHRM5 (HGNC:1954) and cauda equina syndrome with neurogenic bladder (MONDO:0020767). The case reports and multi‐patient studies both describe a single patient harboring a homozygous missense variant in CHRM5, suggesting a potential but not yet fully validated link between the gene and the disease phenotype (PMID:37213061). The patient presented with neurogenic bladder accompanied by secondary complications such as hydroureter, vesicoureteral reflux, and chronic kidney disease. Although the clinical presentation overlaps with other congenital anomalies of the kidney and urinary tract, the evidence remains limited in terms of replication and segregation in additional families. This initial observation warrants cautious interpretation until further patients are identified.

The genetic evidence is derived solely from the identification of a homozygous missense variant. In the reported data, the variant is described as p.Gln184Arg; however, no accompanying coding (c.) description meeting HGVS guidelines is available. As such, the variant does not meet the strict criteria for a complete HGVS string and is therefore not included in the formal variant list. Inheritance in this context appears autosomal recessive, as the variant was observed in a homozygous state in the affected individual (PMID:37213061). The limited genetic data, with only one proband reported and no additional affected relatives documented, underscores the need for further genetic confirmation.

Functional assessments in both in vivo and in vitro studies have been conducted to explore the role of CHRM5 in bladder physiology. Expression studies have confirmed that CHRM5 is expressed in both murine and human bladder tissues, and knockout mouse models have provided supportive evidence of bladder overactivity. However, in vitro functional assays did not demonstrate conclusive evidence of pathogenicity that would decisively strengthen the causative role of CHRM5 in neurogenic bladder. These results indicate that while there is biological plausibility in CHRM5's involvement, the experimental evidence remains insufficient to move beyond a tentative role (PMID:37213061). The discordance between animal model findings and cellular assays further emphasizes the need for additional functional validation.

There is an absence of robust segregation data or replication in additional unrelated probands, which weakens the overall confidence in the gene‐disease association. The candidate status of CHRM5 is further challenged by the lack of corroborative evidence from parallel studies, and similar clinical presentations are observed in other genetic conditions affecting the urinary tract. The current evidence does not address potential genetic heterogeneity or secondary modifiers that could contribute to the observed phenotype. As such, the association remains provisional and should be interpreted with caution in diagnostic settings. Further recruitment of cases and comprehensive functional analyses are required to resolve these uncertainties.

Integration of the clinical, genetic, and experimental data yields a coherent narrative that supports a limited association between CHRM5 and cauda equina syndrome with neurogenic bladder. The singular observation of a homozygous missense variant in a patient with a consistent clinical presentation, alongside inconclusive functional studies, suggests that CHRM5 may represent a potential candidate gene. Nonetheless, the scarcity of genetic replication and the incongruence in experimental outcomes limit the current clinical utility of this finding. The reported evidence is hypothesis‐generating rather than confirmatory, and its use in routine diagnostic decision‑making remains premature. This candidate gene requires additional evidence from independent cohorts and further functional studies.

Key Take‑home sentence: While initial observations implicate CHRM5 in cauda equina syndrome with neurogenic bladder, the evidence is limited and additional studies are necessary to establish its clinical validity.

References

• American journal of medical genetics. Part A • 2023 • Recessive CHRM5 variant as a potential cause of neurogenic bladder PMID:37213061

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