DNAAF4 – Primary Ciliary Dyskinesia

DNAAF4 encodes dynein axonemal assembly factor 4, critical for the cytoplasmic preassembly of dynein arms. Mutations in DNAAF4 cause Primary Ciliary Dyskinesia, an autosomal recessive disorder manifesting as chronic sinusitis, bronchiectasis, situs inversus totalis and infertility (HP:0011109; HP:0002110; HP:0001696; HP:0000789).

1. Clinical Validity Assessment

The DNAAF4–PCD association meets ClinGen Strong criteria based on biallelic pathogenic variants in multiple unrelated individuals and concordant functional studies. We count 12 individuals with recessive loss-of-function mutations ([PMID:23872636]) and four unrelated probands with novel missense, splice-site and nonsense alleles ([PMID:36583018], [PMID:37147940], [PMID:35903363]). Experimental concordance across cellular, murine and zebrafish models further supports pathogenicity.

2. Genetic Evidence

Inheritance is autosomal recessive. Sixteen unrelated probands have been reported: twelve with biallelic loss‐of‐function variants in DNAAF4 ([PMID:23872636]), one with homozygous missense c.1118G>A (p.Gly373Glu) ([PMID:36583018]), one with compound splice-site c.784-1G>A and 20.1 kb deletion ([PMID:37147940]), and two with homozygous nonsense variants c.733C>T (p.Arg245Ter) and c.988C>T (p.Arg330Trp) in two individuals ([PMID:35903363]).

3. Segregation

Segregation data are limited to affected probands and carrier parents. Homozygous c.1118G>A co-segregated with disease in a consanguineous pedigree ([PMID:36583018]). No large multiplex families have been reported.

4. Variant Spectrum

Reported variants include missense (n=1), splice-site (n=1), structural deletion (n=1) and multiple loss-of-function alleles (n≥12) such as frameshift and stop-gain. No recurrent or population-specific founder alleles have been documented.

5. Functional Evidence

The p.Gly373Glu missense variant reduces DNAAF4 protein stability without altering expression or interaction with DNAAF2 ([PMID:36583018]). Murine Dyx1c1 (DNAAF4) knockout and ENU models phenocopy PCD with absent outer and inner dynein arms, and zebrafish morpholino knockdown causes laterality and motility defects ([PMID:23872636]). High-speed video microscopy and immunofluorescence confirm dynein arm assembly failure in patient cilia ([PMID:25186273]).

6. Conflicting Evidence

No studies have refuted the DNAAF4–PCD association or assigned alternative phenotypes.

7. Integration & Conclusion

Genetic and experimental data across human, murine and zebrafish systems fulfill ClinGen Strong criteria. DNAAF4 should be included in PCD diagnostic gene panels to guide clinical decision-making and genetic counseling.

Key Take-home: DNAAF4 biallelic variants cause autosomal recessive primary ciliary dyskinesia; testing enables definitive molecular diagnosis and informs management.

References

• Nature Genetics • 2013 • DYX1C1 is required for axonemal dynein assembly and ciliary motility PMID:23872636
• The European respiratory journal • 2014 • Ciliary beat pattern and frequency in genetic variants of primary ciliary dyskinesia PMID:25186273
• Frontiers in genetics • 2022 • Homozygous mutation in DNAAF4 causes primary ciliary dyskinesia in a Chinese family. PMID:36583018
• Asian journal of andrology • 2023 • Identification of a novel splice site mutation in the DNAAF4 gene of a Chinese patient with primary ciliary dyskinesia. PMID:37147940
• • • Title unavailable PMID:35903363

Evidence Based Scoring (AI generated)

Gene–Disease Association Strong 16 probands, multisystem concordant functional data Genetic Evidence Strong Biallelic DNAAF4 variants in 16 unrelated individuals across consanguineous and non-consanguineous families Functional Evidence Moderate Murine and zebrafish models replicate PCD phenotypes; patient ciliary analyses confirm dynein assembly defect