Submission Details

ODAD1, also known as CCDC114, was first reported in relation to Primary Ciliary Dyskinesia in 2013 (PMIDs 23261302 and 23261303). It encodes a coiled-coil domain-containing protein that is an essential component of the outer dynein arm-docking complex required for the correct attachment of the ODA to the microtubule doublet (PMID: 35163670). Reported PCD phenotype in patients with ODAD1 mutations includes decreased nasal nitric oxide, recurrent respiratory tract infections, neonatal respiratory distress, bronchiectasis, and/or situs abnormalities along with ultrastructural ODA defect (PMIDs 23261302 and 23261303). Milder phenotype has been linked to a partially functioning mutant protein which allowed for assembly of some ODAs and a significant level of ciliary activity (PMID: 35163670). 5 (frameshift and splice site) variants that have been reported in 6 probands carrying biallelic ODAD1 mutations are included in this curation (PMIDs: 23261302, 23261303 and 35163670). A conserved haplotype is detected to lie in cis with the 853G>A variant, compatible with being a founder mutation (PMID: 23261303). Segregation analysis in multiple Volendam family members confirmed a consistent recessive pattern of inheritance (PMID: 23261303). Lack of infertility among affected family members is suggested to arise from genetic redundancy as CCDC63 could potentially replace CCDC114 function in sperm (PMID: 23261303). Experimental evidence also supports this gene disease relationship. Expression analysis via RT-PCR reveals that ODAD1 shows high expression in lung and testis (PMID: 23261302). Subcellular localization of ODAD1 protein confirmed its expression along the entire length of human cilia (PMID: 23261303). ODAD1 mutant cilia showed abnormal ciliary motility comprising large areas of static cilia, with occasionally stiff cilia having a twitching or flickering movement that is slow, and ineffective for mucus transport across the epithelial surface (PMID: 23261303). ODAD1 expression in cultured human bronchial cells paralleled the time course of ciliary differentiation and DNAI1 expression which indicates a crucial role in ciliogenesis (PMID: 23261302). The Chlamydomonas orthologue of ODAD1 (Oda1; Dcc2) has been shown to be a component of the outer dynein arm docking complex (ODA-DC) that is essential for the assembly of the ODA (PMID: 11907279).

In summary, ODAD1 is definitively associated with autosomal recessive Primary Ciliary Dyskinesia 20. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld overtime. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 17, 2022 (SOP Version 9).