ODAD2 (ARMC4) was first reported in relation to autosomal recessive primary ciliary dyskinesia 23 (PCD23) with or without situs inversus in 2013 (Hjeij et al., PMID: 23849778). PCD23 is one of 50 primary ciliary dyskinesias that have been observed to be inherited in a monogenic fashion. Most PCD patients present with a chronic productive cough, recurrent respiratory infection, and chronic rhinosinusitis. Some patients also demonstrate situs inversus and neonatal respiratory distress (PMID:23849778).
8 variants (1 missense, 5 nonsense, 1 frameshift, and 1 large deletion) that have been reported in 8 probands across 2 publications (PMIDs: 2389778, 24203976) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. High-speed video microscopy of the respiratory cilia in 4 probands with ODAD2 mutations showed reduced or absent ciliary beating. Transmission electron microscopy of these cilia showed a reduction or lack of outer dynein arms, which suggests that the ODAD2 protein is important for the assembly of the outer dynein arm structure (PMIDs: 23849778, 24203976).
This gene-disease relationship is also supported by biochemical evidence, expression data, model systems, and rescue experiments (PMIDs: 24055424, 27486780, 23715323, 23849778). First, ODAD1 is also involved in the outer dyenin arm docking complex and is definitively associated with PCD20, which supports ODAD2 also having a role in PCD (PMID: 27486780). Secondly, GTEx expression data shows high levels of ODAD2 expression in the lungs, testes, and fallopian tubes, which is consistent with the PCD phenotype (PMID: 27486780). Next, fruit fly and zebrafish model systems demonstrate the respective PCD phenotypes of infertility and situs inversus (PMIDs: 24055424, 23849778). Finally, the situs inversus phenotype in the zebrafish was significantly rescued using a human copy of ODAD2 (PMID:23849778).
In summary, ODAD2 is definitively associated with autosomal recessive primary ciliary dyskinesia 23. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on the meeting date 11/10/2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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