Submission Details

ODAD3 (CCDC151) was first reported in relation to autosomal recessive primary ciliary dyskinesia 30 (PCD30) in (Hjeij et al., PMID: 25192045). PCD30 is one of nearly 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:33242470).

7 variants (3 nonsense, 1 deletion, 2 out-of-frame duplications, and 1 out-of-frame indel) that have been reported in 7 probands in 7 publications (PMIDs: 25192045, 31469207, 32490514, 31213628, 25224326, 33719352, 30504913) are included in this curation. One variant (NM_145045.5:c.925G>T [p.E309*]) is suspected to be a founder variant with origin in the Middle East/Northern Africa (PMID:31469207) despite its absence from gnomAD (v.2.1.1). To date, the p.E309* variant has been observed in 6 patients with PCD30 from 3 families. Of thse 6 patients, 2 were from Egypt, 2 were from Israel, and 2 were reportedly of Arabic/Bedouin ancestry. Only 1 proband with this variant was scored as a part of this curation due to the assertion that p.E309* is a founder variant. 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 LOF.

This gene-disease relationship is also supported by expression studies, biochemical evidence, protein interactions, animal models, and a rescue experiment (PMIDs: 23715323, 25192045, 24067530). First, GTEx data showed high levels of expression of ODAD3 in human tissues associated with PCD (lungs, testis, fallopian tubes) (PMID: 23715323). Next, Jerber et al. demonstrated that Ccdc151 expression was shown to be strongly induced in mouse ependymal cells in vitro during the ciliary differentiation process. The level of expression of Ccdc151 reached almost 7x higher than the comparison protein (Tpb) in ciliogenesis, which strongly suggests that CCDC151 is important for the structure and function of cilia (PMID: 24067530). Hjeij et al. performed a co-immunoprecipitation which showed that ODAD3 interacts physically with ODAD1 in vitro (2019). Furthermore, they showed that the localization of ODAD1 to the ciliary axonnome is dependent on the presence of ODAD3 (PMID:25192045). Since ODAD1 was classified as definitively associated with PCD by the ClinGen Motile Ciliopathy GCEP, it is likely that LOF variants in ODAD3 would result in PCD as well. Hjeij et al. also published a mouse model, zebrafish model, and zebrafish rescue experiment. Mice with the c.828+2T>C Ccdc151 variant (identified within a mutagenesis screen) showed laterality defects as well as immotile cilia in the trachea and brain ventricles. TEM confirmed loss of the ODA in the tracheal cilia of the mice. The zebrafish models contained a c.631T>A (p.Lys211*) variant in ccdc151 which was also discovered as part of a mutagenesis screen. These zebrafish demonstrated laterality defects and kidney cysts. High speed video microscopy revealed ciliary immotility in the developing kidney of the zebrafish. The laterality defects were partially rescued by inserting a wild-type copy of ccdc151 into zebrafish embryos (PMID:25192045).

In summary, ODAD3 is definitively associated with autosomal recessive primary ciliary dyskinesia 30. 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 2/28/2023 (SOP Version 9).