DNAAF6 and Primary Ciliary Dyskinesia

The association between DNAAF6 (HGNC:28570) and primary ciliary dyskinesia (MONDO_0016575) is supported by evidence from case reports and multi‐patient studies demonstrating a strong correlation between DNAAF6 variants and the clinical phenotype. Affected individuals present with a constellation of respiratory symptoms including bronchiectasis, wheezing, glue ear, and chronic sinusitis, features that are classically seen in primary ciliary dyskinesia. These findings emphasize the clinical relevance of DNAAF6 genetic testing for diagnostic decision‑making in patients with suspected ciliary dysfunction.

A pediatric case report identified a copy number variation in DNAAF6 in an 11‑month‑old boy presenting with a productive cough, nasal obstruction, and imaging evidence consistent with primary ciliary dyskinesia (PMID:33812756). Although the report focused on a copy number alteration, it laid the groundwork by confirming structural defects in cilia through transmission electron microscopy, which revealed both outer and inner dynein arm abnormalities. This functional observation is crucial as it correlates well with the pathogenic mechanism attributed to DNAAF6 disruption.

Subsequent multi‑patient studies have expanded the genetic evidence by identifying novel hemizygous DNAAF6 variants in unrelated Han Chinese families. In one study, whole‑exome sequencing revealed a hemizygous missense variant, c.290G>T (p.Gly97Val), and a hemizygous frameshift variant in different families, each leading to protein degradation as confirmed in HEK293T cells (PMID:32170493). The identification of these distinct variants in multiple probands provides strong genetic evidence that pathogenic alterations in DNAAF6 directly disrupt ciliary function.

While explicit segregation data detailing additional affected relatives is limited, the recurrence of DNAAF6 variants in separate families and the consistency of the clinical phenotype across independent studies lend substantial support to a causative relationship. The cumulative genetic findings from both the isolated case report and the multi‑patient studies contribute to the classification of the gene‑disease association as strong. This conclusion is bolstered by concordant functional data that confirm the deleterious impact of the variants on protein stability and ciliary ultrastructure.

Functional assessments have been pivotal in elucidating the pathogenic mechanism of DNAAF6. Experimental studies employing ultrastructural and immunostaining analyses reveal the absence of both outer and inner dynein arms in patient-derived cells, consistent with impaired motile cilia function. In vitro assays in HEK293T cells demonstrated that the DNAAF6 variants, including c.290G>T (p.Gly97Val), induce marked protein degradation, thereby disrupting the assembly of the ciliary complex. These insights provide a mechanistic explanation for the respiratory and reproductive phenotypes associated with the gene.

In summary, the integration of genetic and functional evidence supports a strong association between DNAAF6 and primary ciliary dyskinesia. The identification of pathogenic DNAAF6 variants not only enhances our understanding of the disease mechanism but also informs diagnostic evaluation and potential therapeutic interventions. Key take‑home: Establishing the DNAAF6 variant status in patients with ciliary dyskinesia can significantly impact clinical management, offering a pathway for precise diagnosis and optimized patient care.

References

• Auris, nasus, larynx • 2022 • A pediatric case of primary ciliary dyskinesia caused by novel copy number variation in PIH1D3 PMID:33812756
• Journal of assisted reproduction and genetics • 2020 • Novel DNAAF6 variants identified by whole-exome sequencing cause male infertility and primary ciliary dyskinesia PMID:32170493

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