Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
This summary reviews the association between CFAP54 and primary ciliary dyskinesia, a recessively inherited disorder characterized by impaired ciliary function. Multiple lines of evidence support the role of CFAP54 in the pathogenesis of this condition. Case reports and multi‐patient studies reveal that patients harbor compound heterozygous and missense variants in CFAP54, establishing a strong genotype–phenotype correlation (PMID:37725231). The clinical presentation consistently includes hallmark features of primary ciliary dyskinesia, such as hydrocephalus and infertility (PMID:37725231). This evidence supports the diagnostic consideration of CFAP54 variants in patients with PCD symptoms. Overall, the genetic data provide a solid foundation for the clinical validity of this gene–disease relationship.
Genetically, CFAP54 exhibits an autosomal recessive inheritance pattern. In the initial case report, a patient was found to harbor a compound heterozygous set of CFAP54 variants. Notably, one of the pathogenic variants, reported as c.2649_2657delinC (p.Glu883AspfsTer47), exemplifies the deleterious frameshift alteration in the coding region. Additional missense variants further substantiate the gene’s role by demonstrating a consistent in vitro reduction in mRNA expression across patient samples (PMID:37725231). Although extended familial segregation data were not extensively detailed, the recurrence in unrelated probands bolsters the association. This evidence is of high relevance to clinical decision‑making and genetic counseling.
Experimental evidence reinforces the genetic findings. Functional assays, including minigene splicing tests and both knockout and knock‑in mouse models, replicate critical PCD phenotypes such as hydrocephalus, infertility, and mucus accumulation. These studies demonstrate that loss of CFAP54 function leads to impaired ciliary structure and function, aligning with the clinical spectrum observed in patients. In vitro assessments reveal a marked reduction in CFAP54 mRNA when frameshift mutations are present. The in vivo recapitulation of disease phenotypes provides an important mechanistic link between variant effect and pathology (PMID:37725231). Such concordance between molecular studies and clinical data is pivotal for confirming disease causality. Taken together, these experimental validations add robust weight to the overall association.
No significant conflicting evidence has been reported that would dispute the involvement of CFAP54 in primary ciliary dyskinesia. While additional studies have reported CFAP54 mutations in the context of male infertility and related phenotypes, these findings are consistent with the broad clinical spectrum of PCD, which can include reproductive dysfunction. The integration of data from multiple independent studies—ranging from case-based genetic analyses to comprehensive functional assessments—further strengthens the association. Thus, the cumulative evidence exceeds the minimal threshold required for clinical utility.
In summary, both genetic and experimental data converge to support a strong association between pathogenic CFAP54 variants and primary ciliary dyskinesia. The autosomal recessive nature of the disorder, coupled with the identification of deleterious variants and validated functional defects in animal models, positions CFAP54 as a key diagnostic marker for PCD. Clinicians and researchers can leverage this information for precise genetic testing and targeted interventions. Future studies may expand upon these findings, yet the current evidence is already highly supportive of CFAP54 as a disease‐causing gene.
Key Take‑Home Sentence: CFAP54 is strongly implicated in primary ciliary dyskinesia, with converging genetic and functional evidence underpinning its clinical utility in diagnosis and management.
Gene–Disease AssociationStrongCFAP54 variants were identified in at least 2 unrelated probands with PCD (PMID:37725231) and are supported by functional animal models exhibiting key PCD phenotypes such as hydrocephalus and infertility. Genetic EvidenceStrongMultiple variant types, including the frameshift variant c.2649_2657delinC (p.Glu883AspfsTer47) and deleterious missense changes, have been found in unrelated patients, bolstered by recurrence and functional mRNA findings (PMID:37725231). Functional EvidenceStrongRobust experimental data from minigene assays and CFAP54 knockout/knock‑in mouse models demonstrate reduced mRNA expression and reproduce PCD phenotypes, affirming the gene’s role in disease pathogenesis (PMID:37725231). |