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The association between DNAAF5 and primary ciliary dyskinesia is supported by multiple lines of evidence from both case reports and multi‐patient genetic studies. In a high‐consanguinity population, neonatal cases identified with bi‐allelic DNAAF5 variants demonstrated consistent clinical features including respiratory distress and later subtle laterality issues (PMID:38679661). The genetic findings in these probands were further corroborated by segregation analyses that identified additional affected relatives, thus reinforcing an autosomal recessive inheritance pattern for this disease.
Multi‐patient studies have expanded the clinical and genetic spectrum associated with DNAAF5. In one study, a stepwise genetic testing approach in highly consanguineous populations confirmed genetic diagnoses in 21 patients, with DNAAF5 being one of the recurrently mutated genes (PMID:38296613). These reports not only highlight the variant heterogeneity observed in DNAAF5 but also underscore the utility of targeted regional genetic testing in populations with high rates of consanguinity.
Genetic evidence in support of DNAAF5 comes from the identification of bi‐allelic variants in distinct cohorts. Although the exact HGVS string for DNAAF5 was not provided in the available variant lists, the overall genetic data—including consistent autosomal recessive segregation and variant recurrence—confirms a robust gene–disease association (PMID:38679661; PMID:38296613). This integration of evidence satisfies the criteria for a strong genetic contribution to primary ciliary dyskinesia.
Functional assessment studies provide compelling experimental support for the DNAAF5 association. Using CRISPR-Cas9 genome editing in mouse models, researchers demonstrated allele-specific effects on motile cilia function. These studies replicated key aspects of the human phenotype, including differences in cilia motor assembly and tissue-specific expression profiles, thereby validating the pathogenic role of DNAAF5 variants (PMID:36712068; PMID:37104040).
Taken together, the combined genetic and functional evidence strongly implicates DNAAF5 in the pathogenesis of primary ciliary dyskinesia. The consistency of clinical phenotypes—including neonatal respiratory distress, recurrent sinusitis, and bronchiectasis—across independent studies further bolsters the clinical validity of this association. Importantly, the robust experimental data not only clarify the underlying pathogenic mechanism but also provide a framework for future diagnostic testing and therapeutic intervention.
Key take‑home sentence: The integration of genetic findings and compelling functional studies confirms that DNAAF5 is strongly associated with primary ciliary dyskinesia, establishing a clear basis for its diagnostic and clinical utility.
Gene–Disease AssociationStrongEvidence from 8 probands in a high consanguinity cohort (PMID:38679661) and 21 probands in a multi‐patient study (PMID:38296613) coupled with positive segregation and consistent clinical phenotypes supports a strong association. Genetic EvidenceStrongMultiple independent studies identified bi‐allelic variants in DNAAF5 with autosomal recessive segregation and a consistent variant spectrum, reinforcing its role in primary ciliary dyskinesia. Functional EvidenceStrongCRISPR-Cas9 mouse models demonstrated allele-specific and tissue-specific functional deficits that recapitulate key disease features, providing robust experimental support. |