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The genetic association between ODAD1 and primary ciliary dyskinesia is supported by multiple independent case reports and international cohort studies. Several studies have identified ODAD1 variants in patients presenting with respiratory dysfunction, laterality defects, and renal anomalies—a spectrum highly consistent with ciliopathy manifestations. Notably, the c.707C>T (p.Ala236Val) variant has been reported in a patient with a complex phenotype, exemplifying the type of recurrent pathogenic change observed (PMID:30291279). These findings, replicated across distinct populations, underscore a robust relationship between ODAD1 and the disease. The convergent genetic data have therefore positioned this association within the ClinGen “Strong” category. In addition, segregation analyses in affected families further solidify this link.
The genetic evidence comprises a diverse variant spectrum that includes missense, nonsense, and splice-site changes. For instance, in addition to the c.707C>T (p.Ala236Val) variant, other reports detail variants such as c.584T>C (p.Leu195Pro) and compound splice-site alterations. Affected individuals, typically from autosomal recessive families, exhibit a consistent clinical picture that aligns with primary ciliary dyskinesia features. This multiplicity of variant types, observed in at least 4 unrelated probands (PMID:30291279), supports a “Strong” genetic evidence score. The reproducibility of these findings in diverse ethnic backgrounds underlines the clinical relevance of ODAD1 testing for diagnostic decision‑making.
Functional studies further enhance the evaluative framework for this gene-disease association. Experimental assays, including analyses of nasal epithelial cells and knockdown models, have demonstrated that splice-site mutations (for example, c.1502+5G>A) result in truncated proteins that retain partial function. This residual activity appears to correlate with the milder phenotypes observed in certain cases and provides key mechanistic insights into ODAD1-related dysfunction. Although the functional data are not as numerically extensive as the genetic reports, they contribute a “Moderate” tier of functional evidence by confirming that the molecular consequences of these mutations are concordant with the clinical spectrum of primary ciliary dyskinesia (PMID:35163670).
While some variability in clinical presentation has been noted among patients carrying ODAD1 mutations, no studies have presented strong conflicting evidence to dispute the association. Minor differences in phenotypic features suggest that additional modifiers may influence disease severity, yet the core pathogenic role of ODAD1 remains unchallenged. This integrated genetic and experimental evidence not only reinforces the association but also provides clinicians with a robust framework for patient diagnosis and management. Critical to precise genetic counseling, these findings support the implementation of ODAD1 variant screening as part of the diagnostic workup for primary ciliary dyskinesia.
In summary, the association between ODAD1 and primary ciliary dyskinesia is underpinned by extensive genetic data from multiple unrelated probands alongside functional studies demonstrating a consistent molecular mechanism. The autosomal recessive inheritance pattern, together with segregation data and functional validation, affirms the clinical utility of ODAD1 testing. This comprehensive evidence base aids diagnostic decision‑making, supports commercial development of genetic tests, and provides a foundation for future publication and research in ciliopathies.
Key take‑home: ODAD1 variant analysis is an invaluable diagnostic tool that improves patient management and advances our understanding of primary ciliary dyskinesia.
Gene–Disease AssociationStrongAt least 4 independent probands from distinct studies (PMID:30291279) and consistent segregation assessments support the association between ODAD1 and primary ciliary dyskinesia. Genetic EvidenceStrongMultiple variant types, including the recurrent c.707C>T (p.Ala236Val) and various splice-site mutations, have been identified in unrelated individuals, reinforcing pathogenicity (PMID:30291279). Functional EvidenceModerateFunctional assays demonstrate that splice-site mutations such as c.1502+5G>A produce truncated proteins with partial function, aligning with the mild phenotypes observed (PMID:35163670). |