ODAD2 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD; MONDO:0016575) is an autosomal recessive disorder characterized by impaired motile cilia, leading to chronic respiratory infections, bronchiectasis and laterality defects. ODAD2 (HGNC:25583), also known as ARMC4, encodes an axonemal assembly factor critical for outer dynein arm (ODA) docking and ciliary motility.

Genetic evidence for ODAD2 in PCD includes biallelic pathogenic variants in at least 14 unrelated probands: twelve individuals with frameshift or nonsense alleles in ODAD2 ([PMID:23849778]), one consanguineous case with a missense or splice defect identified by WES and runs of homozygosity ([PMID:28801648]), and one pediatric patient carrying a missense allele (c.2306C>A (p.Pro769His)) in a Chinese cohort ([PMID:33577779]). A recurrent nonsense variant, c.866C>A (p.Ser289Ter), has been documented in PCD patients.

Phenotypically, ODAD2‐related PCD presents with neonatal respiratory distress (HP:0002643), recurrent respiratory infections (HP:0002205), chronic sinusitis (HP:0011109), bronchiectasis (HP:0002110), dextrocardia (HP:0001651), infertility (HP:0000789) and chronic pulmonary obstruction (HP:0006510). Carrier frequency estimates are not yet defined.

Functional studies demonstrate that patient respiratory epithelial cells show markedly reduced ODAs on transmission electron microscopy, resulting in severely impaired ciliary beating ([PMID:23849778]). Transient knockdown in zebrafish and analysis of an ENU mouse model confirm that ODAD2 deficiency recapitulates laterality defects and ciliary dysmotility, establishing a loss-of-function mechanism.

No conflicting reports disputing ODAD2 in PCD are currently known. The concordance of human genetics, ultrastructural phenotype and animal models provides strong clinical validity for ODAD2 as a PCD gene.

Integrating genetic and experimental data supports a definitive autosomal recessive mechanism: ODAD2 loss-of-function alleles cause PCD by disrupting ODA assembly. Clinical genetic testing for ODAD2 variants enhances diagnostic yield and informs genetic counselling.

Key Take-home: Biallelic ODAD2 (ARMC4) loss-of-function variants cause autosomal recessive PCD with classic respiratory and laterality phenotypes, and should be included in diagnostic panels.

References

• American journal of human genetics • 2013 • ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry. PMID:23849778
• Scientific reports • 2017 • An effective combination of whole-exome sequencing and runs of homozygosity for the diagnosis of primary ciliary dyskinesia in consanguineous families. PMID:28801648
• Chest • 2021 • Clinical and Genetic Spectrum of Children With Primary Ciliary Dyskinesia in China. PMID:33577779

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