Respiratory ciliopathies including non-CF bronchiectasis

Gene: WFDC2

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before changing the rating. One GLH notes that this gene is associated with bronchiectasis and not PCD and further discussion is required.

Created: 11 Dec 2025, 4:33 p.m. | Last Modified: 11 Dec 2025, 4:33 p.m.

Panel Version: 4.50

Green List (high evidence)

Comment on list classification: As reviewed by Steven Cowman, there is sufficient evidence available (10 unrelated families) for the association of this gene with green rating in the next GMS update.

Created: 19 Sep 2024, 10:34 a.m. | Last Modified: 19 Sep 2024, 10:34 a.m.

Panel Version: 3.17

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
bronchiectasis, MONDO:0004822; Nasal polyposis, HP:0100582

Publications

• 38626355

Green List (high evidence)

In addition to the 11 individuals reported in PMID 38626355 (see earlier review) there is now a further report (PMID 40401042) of three unrelated individuals from Japan with bronchiectasis who were all found to be homozygous for the same missense variant of WFDC2 (p.Cys97Trp).

In keeping with the first series, all patients were reported to have upper lobe predominant bronchiectasis, sinus disease and low nasal NO, although ciliary ultrastructure was normal on EM and no pathogenic variants in CFTR or PCD-causing genes were found.

Created: 3 Jun 2025, 2:41 p.m. | Last Modified: 3 Jun 2025, 2:41 p.m.

Panel Version: 4.1

Reported in 11 individuals from 10 different families, all of whom had nasal polyposis and nine with diffuse bronchiectasis, aged between 7 and 52 years. All those tested had impaired lung function (8/11) and Pseudomonas isolation (8/11). The bronchiectasis was noted to have an upper-lobe predominance in a manner similar to CF.

Low nasal NO levels were reported in all (9/11) tested individuals, although no disease causing variants were found in CFTR or PCD-related genes and mucociliary studies found clearance within the normal range, and EM in 8 individuals found normal ciliary ultrastructure. Sweat chloride was normal in all (9/11) tested individuals.

Seven pathogenic WFDC2 variants were found, with one missense variant (c.145T>C; p.Cys49Arg) found in 12/22 alleles from 8/11 individuals. Expression analysis of healthy controls found WFDC2 to be expressed in the respiratory epithelium. Glycosylated WFDC2 protein was detectable in the saliva of a healthy control and one heterozygous mother of an affected individual, but not three tested affected individuals. Structural analysis suggested the c.145T>C mutation disrupts N-linked glycosylation of WFDC2 and hence impairs secretion.
Sources: Literature

Created: 13 Sep 2024, 10:22 a.m. | Last Modified: 3 Jun 2025, 2:33 p.m.

Panel Version: 4.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
bronchiectasis; nasal polyposis

Publications

• PMID: 38626355
• 40401042