Respiratory ciliopathies including non-CF bronchiectasis

Gene: CFAP46

Red List (low evidence)

Comment on list classification: There is only one case reported with biallelic CFAP46 SNVs and respiratory phenotype. There is also functional evidence available in support of the association. However, these are high frequency variants with homozygotes in gnomAD.

Hence, this gene is rated red with the current evidence.

Created: 17 Jul 2025, 2:35 p.m. | Last Modified: 17 Jul 2025, 2:35 p.m.

Panel Version: 4.42

PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene. As reviewed by Zornitza Stark below, the authors speculate that LEFTY1 variant might be responsible for the phenotype.

PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus.

In addition, this gene-disease association is supported by Chlamydomonas reinhardtii null mutant model (PMID:22573824) and gene expression data (PMID:23715323). In addition, immunofluorescence microscopy analyses of respiratory epithelial cells show that CFAP46 localises along the entire ciliary axoneme in healthy individuals but is lost in the respiratory cells of a CFAP46-PCD patient (PMID:39362668).

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.

Created: 3 Apr 2025, 1:31 p.m. | Last Modified: 17 Jul 2025, 4:23 p.m.

Panel Version: 4.42

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
primary ciliary dyskinesia, MONDO:0016575

Publications

• 22573824
• 23715323
• 29843777
• 39362668

I don't know

One report of a 22 year old male born to non-consanguineous parents who had chronic respiratory symptoms, bronchiectasis, chronic rhinitis and hearing and ear symptoms. He had situs solitus and normal nNO. Semen analysis reported reported
normozoospermia (but did not exclude subtle swimming defects).

He was found to be compound heterozygous for LOF variants c.19C>T, p.Gln7Ter and c.7286-2A>G, p.Glu2429Gly_Met2430insfsTer9. Immunofluorescence found absent staining for CFAP46 in ciliary axonemes and the protein was not detectable in axonemal/cytoplasmic protein extract. He had situs solitus and normal nNO. Ciliary studies found normal EM and HSMVA although there was evidence of reduced ciliary transport on a fluorescent particle assay.

Created: 18 Mar 2025, 3:41 p.m. | Last Modified: 18 Mar 2025, 3:41 p.m.

Panel Version: 3.25

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Primary ciliary dyskinesia

Publications

• 39362668

Red List (low evidence)

Submitted on behalf of NHS GMS "We have been sequencing this gene for the past 2-3 years and have not yet found a clearly pathogenic variant in any PCD patients."

Created: 8 Mar 2022, 11:15 a.m. | Last Modified: 8 Mar 2022, 11:15 a.m.

Panel Version: 1.55

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 11:15 a.m. | Last Modified: 8 Mar 2022, 11:15 a.m.

Panel Version: 1.55

This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Aside from the evidence provided by Zornitza Stark there does not appear to be any other evidence to support this gene-disease association.

Created: 2 Dec 2020, 1:05 p.m. | Last Modified: 2 Dec 2020, 1:05 p.m.

Panel Version: 1.26

Red List (low evidence)

A single individual reported with a heterotaxy syndrome, but a multigenic CNV duplication. Authors also speculate the phenotype of this patient may be caused by a mutation in the LEFTY1 gene (no pathogenic missense for this gene are listed in ClinVar). Additionally, Zebrafish knockout had no phenotype.

Created: 25 May 2020, 6:33 a.m. | Last Modified: 25 May 2020, 6:33 a.m.

Panel Version: 1.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Heterotaxy

Publications

• 29843777

I don't know

Initial gene list and info collated by Ian Berry Leeds Genetics Laboratory November 2018 on behalf of the GMS Respiratory specialist test group. Gene Symbol submitted: CFAP46; Suggested initial gene rating: Amber; Evidence for inclusion: Very good biological candidate gene; Evidence for exclusion: Not reported yet in humans.; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 5 Dec 2018, 1:54 p.m.