Respiratory ciliopathies including non-CF bronchiectasis

Gene: FOXJ1

Green List (high evidence)

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

Created: 4 Dec 2024, 5:04 p.m. | Last Modified: 4 Dec 2024, 5:04 p.m.

Panel Version: 3.23

Comment on list classification: As reviewed by Steven Cowman, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.

Created: 8 Dec 2023, 8:56 p.m. | Last Modified: 8 Dec 2023, 8:56 p.m.

Panel Version: 3.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Initial report of six individuals with bronchiectasis, chronic rhinosinusitis and hydrocephalus of whom three displayed situs inversus, all of whom were found to be heterozygous for variants predicted to result in a premature stop codon. The respiratory epithelia displayed reduced numbers of cilia with an abnormal beating pattern unable to generate fluid flow and EM found a defect in basal body docking defect.

A second report of a four year old child hydrocephalus, rhinitis and repeated lower respiratory tract infections, situs inversus. She was found to be heterozygous for a frameshift variant c.734–735 ins20. Neither parent was found to carry the variant. She did not undergo a respiratory epithelial biopsy.

A third report describes an adult with chronic cough and bronchiectasis, sinus disease, situs inversus and hydrocephalus who was found to be heterozygous for a frameshift variant caused by a single nucleotide deletion at c.709delC (p.Arg237Glyfs*5) in exon 3. A nasal biopsy was unsuitable for EM.

Created: 23 Nov 2023, 2:01 p.m. | Last Modified: 23 Nov 2023, 2:01 p.m.

Panel Version: 3.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Motile ciliopathy; situs inversus; hydrocephalus

Publications

• 31630787
• 37469238
• 37813609

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.

Created: 8 Mar 2022, 11:15 a.m. | Last Modified: 8 Mar 2022, 11:21 a.m.

Panel Version: 1.55

Comment on list classification: This gene is associated with a relevant phenotype in OMIM. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.

Created: 2 Dec 2020, 2:30 p.m. | Last Modified: 2 Dec 2020, 2:30 p.m.

Panel Version: 1.34

Green List (high evidence)

PMID 31630787 - Six unrelated individuals with de novo variants in this gene. Patients have hydrocephaly, bronchiectasis and respiratory disease. Situs inversus was shown in 3/6 patients.
Electron microscopy of demonstrated cilia were unable to general fluid flow and were less frequent on cells. All reported variants were truncating mutations affecting the last exon in the protein, therefore loss of function may not be the mechanism of pathogenicity

Created: 25 May 2020, 7:16 a.m. | Last Modified: 25 May 2020, 7:16 a.m.

Panel Version: 1.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry

Publications

• 31630787

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: New gene added by external reviewer after panel sign off to V1.0- to be reviewed at next panel update with the respiratory Test Group for GMS

Created: 12 Nov 2019, 10:41 a.m. | Last Modified: 12 Nov 2019, 10:41 a.m.

Panel Version: 1.1

I don't know

Wallmeier et al 2019 report the first known cause of autosomal dominant 'PCD' - referred to here more as a motile ciliopathy, than strictly PCD, because there are reduced cilia numbers but no structural changes in the cilia axonemes which are typical for diagnosing PCD. The reported mutations are associated in this sole paper with haploinsufficiency. Wallmeier et al report FOXJ1 mutations in 6 unrelated patients - all were heterozygous, single de novo variants.
Sources: Literature

Created: 5 Nov 2019, 1:48 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Motile ciliopathy; situs inversus, hydrocephalus

Publications

• PMID: 31630787

Mode of pathogenicity
Other