ODAD4

protein-coding

outer dynein arm docking complex subunit 4, the group of Outer dynein arm docking complex subunits|Tetratricopeptide repeat domain containing

Gene summary

This gene encodes a tetratricopeptide repeat domain-containing protein that localizes to ciliary axonmenes and plays a role in the docking of the outer dynein arm to cilia. Mutations in this gene cause severely reduced ciliary motility and the disorder CILD35 (ciliary dyskinesia,primary, 35). Primary ciliary dyskinesia is often associated with recurrent respiratory infections, immotile spermatozoa, and situs inversus; an inversion in left-right body symmetry. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

Previous symbols:

TTC25

MANE transcript

NM_031421.5

Inheritance

AR, AD

ClinVar variants

P:13U:56B:9

Top phenotype

Ciliary dyskinesia, primary, 35

Max pathogenic AF

—

Genomic locus

chr17:41,930,617-41,966,503

External References & Databases

Ensembl (ENSG00000204815)

Transcript & Mutation Effects

hg38 • Region Span ~35.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary ciliary dyskinesia 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014910

Submitter: Labcorp Genetics (formerly Invitae)

primary ciliary dyskinesia 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014910

Submitter: G2P

primary ciliary dyskinesiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

primary ciliary dyskinesia 35DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014910

Submitter: ClinGen

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).

primary ciliary dyskinesia 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014910

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Ciliary dyskinesia, primary, 35AR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Pulmonary

Rationale: Pulmonary and audiologic surveillance may be beneficial to assess respiratory and hearing function and institute early management measures; In order to facilitate mucus clearance, aggressive interventions (eg, chest percussion and oscillatory vest), as well as vaccinations and early and aggressive treatment of respiratory infections may be beneficial, though measures including lobectomy or lung transplantation may be necessary; Individuals may require surgery or other interventions related to congenital cardiac malformations

Refs: 27486780

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ODAD4 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 51

Primary ciliary dyskinesia 35Total: 12

ODAD4-related disorderTotal: 9

not providedTotal: 5

Primary ciliary dyskinesiaTotal: 1

not specifiedTotal: 1

HeterotaxyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031421.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				4 clinvar		4
missense		1 clinvar	54 clinvar	5 clinvar		60
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift	4 clinvar	1 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	1 clinvar			6
Total	7	6	56	9	0	78

Highest pathogenic variant AF is 0.0002222032

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031421.5	RefSeq	NP_113609.1	12	MANE Select
ENST00000377540.6	Ensembl	ENSP00000478589.1	12	MANE Select
NM_001350319.2	RefSeq	NP_001337248.1	11	Standard
ENST00000585530.1	Ensembl	ENSP00000479460.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ttc25	Danio rerio	Structure: otolith Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

ttc25

Danio rerio

Structure: otolith

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Molecular Function

protein binding

Cellular Component

cytoplasm
cytoskeleton
cell projection

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for the docking of the outer dynein arm to cilia, hence plays an essential role in cilia motility. {ECO:0000269|PubMed:27486780}.;

Essentials

Indispensability pred.: N
Indispensability score: 0.351