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| Respiratory ciliopathies including non-CF bronchiectasis v5.4 | CA12 |
Matthew Edwards gene: CA12 was added gene: CA12 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Expert Review Mode of inheritance for gene: CA12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CA12 were set to PMID: 26911677; PMID: 35359895 Phenotypes for gene: CA12 were set to isolated hyperchlorhidrosis Review for gene: CA12 was set to AMBER Added comment: Gene confirmed to cause isolated hyperchlorhidrosis (OMIM#143860), which has been reported to mimic atypical Cystic Fibrosis (CF) - can cause elevated sweat chloride. Some variants associated with gene only cause isolated hyperchlorhidrosis, with no lung involvement, but some associated with broader hentypic spectrum affecting respiratory tract: BESC1 (Bronchiectasis with or without elevated sweat chloride 1). PMID: 26911677 describe two unrelated pedigrees with bi-allelic LOF variants in CA12. One proband: failure to thrive at 2-3 months of age, with sweat chlorides of 82-88mEq/L, with patient mis-diagnosed as having CF rising to 112-16 mEq/L at 9 years of age in one proband. Other phenotypic features: persistent cough, pseudomonas cultures. Other proband: presented at 6 years of age with a history of hyponatremic dehydration and elevated sweat chloride (90-110 mEq/L), with his sister showing a swet chloride of 130mEq/L (iin second pedigree though, there was no lung phenotype). Both sibs were homozygous for a novel missense variant. Obviously limited evidence for patients with lung phenotype currently, but gene should be considered for panel as possible differential in ?CF patients with no CFTR variants detected. Sources: Expert Review |
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| Respiratory ciliopathies including non-CF bronchiectasis v4.1 | WFDC2 |
Steven Cowman edited their review of gene: WFDC2: Added comment: 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.; Changed publications to: PMID: 38626355, 40401042 |
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| Respiratory ciliopathies including non-CF bronchiectasis v4.1 | WFDC2 |
Steven Cowman changed review comment from: 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; to: 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 |
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| Respiratory ciliopathies including non-CF bronchiectasis v3.14 | WFDC2 |
Steven Cowman gene: WFDC2 was added gene: WFDC2 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature Mode of inheritance for gene: WFDC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WFDC2 were set to PMID: 38626355 Phenotypes for gene: WFDC2 were set to bronchiectasis; nasal polyposis Review for gene: WFDC2 was set to GREEN Added comment: 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 |
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| Respiratory ciliopathies including non-CF bronchiectasis v1.43 | CFTR | Matthew Edwards reviewed gene: CFTR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respiratory ciliopathies including non-CF bronchiectasis v0.34 | CFTR |
Louise Daugherty Mode of inheritance for gene CFTR was changed from to BIALLELIC, autosomal or pseudoautosomal Added phenotypes Cystic Fibrosis; Ciliopathies; Congenital bilateral absence of vas deferens, 277180; Sweat chloride elevation without CF; Cystic fibrosis, 219700; {Hypertrypsinemia, neonatal}; {Bronchiectasis with or without elevated sweat chloride 1, modifier of}, 211400; Bronchiectasis; {Pancreatitis, idiopathic}, 167800 for gene: CFTR |
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| Respiratory ciliopathies including non-CF bronchiectasis v0.3 | CFTR |
Louise Daugherty Source Expert Review Green was added to CFTR. Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| Respiratory ciliopathies including non-CF bronchiectasis v0.2 | CFTR | Louise Daugherty reviewed gene: CFTR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respiratory ciliopathies including non-CF bronchiectasis v0.1 | CFTR |
Louise Daugherty gene: CFTR was added gene: CFTR was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: NHS GMS Mode of inheritance for gene: CFTR was set to |
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