Submission Details

The ODAD4 gene, also known as TTC25, was first identified as a potential gene linked to primary ciliary dyskinesia 35 (PCD 35) by Wallmeier et al. in 2016 (PMID: 27486780). PCD 35 is a distinct disease entity (MONDO: 0014910, OMIM # 617092), one of at least 50 monogenic causes of primary ciliary dyskinesias (PCD). The onset of disease symptoms can occur as early as at birth (Backman et al., 2021, PMID: 33746037, Emiralioğlu et al., 2020, PMID: 31765523). Clinical features among well-characterized newborn patients with disease-causing ODAD4 variants include neonatal respiratory distress, while recurrent pneumonia is common in early childhood and later life. Chronic rhinitis, recurrent sinusitis, and nasal polyps are also reported. In addition, a subset of patients exhibit situs inversus or another form of reversed organ laterality or heterotaxy (Wallmeier et al., 2016, PMID: 27486780). Older patients can also exhibit bronchiectasis. Nasal nitric oxide levels are very low or absent in these patients. Diagnostic features of PCD associated with disease-causing ODAD4 variants include abnormal ciliary ultrastructure with an absence or defect of outer dynein arms (ODA) and its docking complex (ODA-DC) in the ciliary axonemes.

This curation has recorded five different probands with PCD 35 harboring suspected deleterious ODAD4 variants. Four variants were scored in these five probands, four of whom had homozygous loss-of-function variants identified. The reported variants included a homozygous splice-site G-to-T transversion in intron 1 of ODAD4, two homozygous frameshift variants, and a homozygous nonsense variant in exon 6 of 12, collectively reported in 4 publications (PMID: 27486780, 2016; PMID: 31765523, 2020; PMID: 33746037, 2021, PMID: 34215651, 2022). Cross-sections of respiratory cilia from patients harboring these ODAD4 gene variants showed absence of the outer dynein arms. All probands harbored biallelic homozygous variants that were confirmed to be in trans. The molecular mechanism appears to be biallelic loss-of-function with an autosomal recessive mode of inheritance, characterized in at least some cases by variants predicted to trigger the absence of a gene product.

This gene-disease relationship is also supported by experimental evidence. High levels of ODAD4 expression in humans are specific to tissues that harbor multi-ciliated cells, particularly the testis and lung (PMID 24309898). Loss of ODAD4 from the cilia of patients harboring other forms of PCD has been described and supports the functional role of ODAD4 in outer dynein arm docking assembly complex machinery (PMID: 27486780, PMID: 17961536). Yeast two-hybrid and reciprocal co-immunoprecipitation showed that ODAD4 interacts with CCDC114, consistent with functional evidence indicating that ODAD4 is essential for the assembly of ODA-DC proteins. This is consistent with analysis of respiratory cells from patients exhibiting loss of ciliary ODAs and an absence of the ODA docking complex, including its components CCDC114, CCDC151, and ARMC4. Loss of ODAD4 led to failure to facilitate recruitment of these ODA-DC proteins to ciliary axonemes (PMID: 27486780, PMID: 17961536).

A mouse model of ODAD4 (Ttc25) deficiency with exon 2 and 3 deletion resulted in immotile nodal cilia and a lack and/or defect of the outer dynein arm docking machinery, as well as hydrocephalus and randomization of left-right body asymmetry (PMID: 27486780). In addition, the Xenopus Ttc25 knockdown showed a failure of ciliary beating, laterality defects, and absent outer dynein arms in axonemes (PMID: 27486780). The mouse and Xenopus models of ODAD4 loss of function both reproduce the typical ultrastructural defects in the outer dynein arms of the ciliary axoneme characteristic of human patients, as well as phenotypes such as ciliary immotility and laterality defects (PMID: 27486780). These phenotypic features are consistent with the pathogenicity of ODAD4 loss of function variants in PCD-35 patients.

In summary, ODAD4 is definitively associated with primary ciliary dyskinesia 35. This has been repeatedly demonstrated in both clinical diagnostic and research settings and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification has been approved by the ClinGen Motile Ciliopathy GCEP on December 8th, 2022 (SOP Version 9).