DNAAF2 – Primary Ciliary Dyskinesia

The association between DNAAF2 and primary ciliary dyskinesia (PCD) is supported by multi‐source evidence including case reports, family segregation studies, and functional assays. Evidence from several independent studies demonstrates that individuals with PCD harbor biallelic alterations in DNAAF2, reflecting an autosomal recessive inheritance pattern. Robust clinical findings, including classic PCD phenotypes such as chronic respiratory infections and laterality defects, have been consistently observed in affected families (PMID:32638265).

Genetic evidence encompasses compound heterozygous and homozygous variants identified in distinct families. In one seminal case, two novel compound heterozygous DNAAF2 mutations were identified in a Han Chinese family, one of which is reported as c.156C>A (p.Tyr52Ter) (PMID:32638265). Additional studies reported DNAAF2 variants detected in consanguineous families, with affected siblings demonstrating segregation of the mutant alleles (PMID:34785929). Together, these findings provide compelling genetic confirmation of the gene‐disease association.

Segregation analysis in these families further supports the contribution of DNAAF2 to the PCD phenotype. Multiple unrelated probands, including a three‐generation family and consanguineous pedigrees, have been documented, with clear autosomal recessive transmission patterns. The presence of additional affected relatives with segregating variants further strengthens the link between DNAAF2 mutations and the clinical manifestations of PCD (PMID:34785929).

The variant spectrum in DNAAF2 is diverse and includes nonsense, frameshift, and missense changes which collectively result in loss of function. The reported c.156C>A (p.Tyr52Ter) mutation, among others, disrupts the protein’s critical role in the cytoplasmic preassembly of dynein arms, thereby impairing ciliary motility. These molecular disruptions align well with the observed clinical symptoms such as bronchiectasis, sinusitis, and laterality defects (PMID:32638265; PMID:34785929).

Functional and experimental studies provide additional support for DNAAF2 pathogenicity. In mouse models, a null allele of Dnaaf2 leads to embryonic lethality and laterality defects, thereby recapitulating key aspects of the human PCD phenotype (PMID:31107948). Moreover, in vitro assays have demonstrated that loss of DNAAF2 function results in defective dynein arm assembly, correlating with impaired ciliary motility. Complementary studies using zebrafish and immunostaining of respiratory tissues further validate the essential functional role of DNAAF2 in cilia formation (PMID:23872636).

In summary, diverse lines of evidence from detailed genetic analyses, family segregation, and robust functional studies converge on DNAAF2 as a causative gene for primary ciliary dyskinesia. The integration of these data not only reinforces the clinical validity of the association but also underscores its importance in diagnostic decision-making and genetic counseling. Key take‑home message: DNAAF2 mutation screening is critical in patients with PCD, and its identification informs both prognostic assessment and tailored management strategies.

References

• Journal of assisted reproduction and genetics | 2020 | Novel compound heterozygous DNAAF2 mutations cause primary ciliary dyskinesia in a Han Chinese family PMID:32638265
• Pharmacogenomics and personalized medicine | 2021 | Identification of Two Novel DNAAF2 Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia PMID:34785929
• Human molecular genetics | 2019 | A null allele of Dnaaf2 displays embryonic lethality and mimics human ciliary dyskinesia PMID:31107948
• Nature genetics | 2013 | DYX1C1 is required for axonemal dynein assembly and ciliary motility PMID:23872636

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