DNAH5 – primary ciliary dyskinesia

DNAH5 encodes an axonemal dynein heavy chain essential for outer dynein arm (ODA) assembly in motile cilia. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder; biallelic DNAH5 variants have been identified in 30 independent probands ([PMID:16627867]) and in 19 probands in a Belgian cohort ([PMID:38602513]), with segregation demonstrated in a family of two affected siblings ([PMID:27988889]).

Genetic evidence includes a spectrum of loss-of-function alleles (nonsense, frameshift, splice) predominantly clustering in five hotspot exons, consistent with autosomal recessive inheritance. The recurrent c.5983C>T (p.Arg1995Ter) variant and multiple compound heterozygous mutations have been documented across diverse populations, including founder alleles in North America and Tunisia.

The clinical phenotype encompasses chronic sinusitis (HP:0011109), recurrent bronchiectasis (HP:0002110), and laterality defects such as situs inversus totalis (HP:0001696). Pulmonary function is variably impaired, with neonatal respiratory distress reported in a subset of patients, and infertility observed in males due to sperm flagellar ODA defects.

Functional studies demonstrate that DNAH5 deficiency disrupts ODA docking and axonemal structure. Patient respiratory epithelial cells and hiPSC-derived airway organoids exhibit complete or distal absence of ODA heavy chains, with rescue and co-immunoprecipitation assays confirming interaction defects in the ODA docking complex ([PMID:30148830]).

No significant conflicting evidence has been reported. The cumulative genetic and experimental data meet clinical validity criteria for a Definitive gene–disease association, with Strong genetic evidence and Moderate functional support.

Key Take-home: Biallelic loss-of-function DNAH5 variants reliably diagnose autosomal recessive PCD, informing early genetic testing strategies to guide respiratory management and genetic counseling.

References

• American journal of respiratory and critical care medicine • 2006 • DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. PMID:16627867
• Lung • 2024 • Genetic Spectrum and Clinical Characteristics of Patients with Primary Ciliary Dyskinesia: a Belgian Single Center Study. PMID:38602513
• PLoS genetics • 2018 • Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility. PMID:30148830
• Journal of assisted reproduction and genetics • 2017 • Clinical and genetic analysis of a family with Kartagener syndrome caused by novel DNAH5 mutations. PMID:27988889

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