Alternative titles; symbols
ORPHA: 60033; DO: 0080526, 9563;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q31.2 | {Bronchiectasis with or without elevated sweat chloride 1, modifier of} | 211400 | Autosomal dominant | 3 | CFTR | 602421 |
| 16p12.2 | Bronchiectasis with or without elevated sweat chloride 1 | 211400 | Autosomal dominant | 3 | SCNN1B | 600760 |
A number sign (#) is used with this entry because of evidence that bronchiectasis with or without elevated sweat chloride-1 (BESC1) is caused by heterozygous mutation in the gene encoding the beta subunit of the epithelial sodium channel (SCNN1B; 600760) on chromosome 16p12.
Bronchiectasis with or without elevated sweat chloride-1 (BESC1) is characterized by dilation of the airways arising from chronic bronchial inflammation accompanied by chronic cough, purulent sputum, and recurrent respiratory tract infections. Severity is variable, and some patients may be identified in adulthood and have normal respiratory function (Sheridan et al., 2005, Fajac et al., 2008).
Genetic Heterogeneity of Bronchiectasis with or without Elevated Sweat Chloride
Bronchiectasis with or without elevated sweat chloride-2 (BESC2; 613021) is caused by mutation in the gene encoding the alpha subunit of the epithelial sodium channel (SCNN1A; 600228) on chromosome 12p13, and BESC3 (613071) is caused by mutation in the gene encoding the gamma subunit (SCNN1G; 600761) on chromosome 16p12.
Bronchiectasis and elevated sweat chloride associated with pancreatic exocrine dysfunction and infertility are also features of cystic fibrosis (CF; 219700), which is caused by mutation in the CFTR gene (602421).
Danielson et al. (1967) found 4 of 5 sibs (2 male, 2 female) affected with bronchiectasis of the middle lobe. Hoo (1979) observed middle lobe bronchiectasis in a brother and sister from a sibship of 7. Bronchiectasis was in the past a common disorder. With the declining prevalence of tuberculosis, development of vaccines to prevent measles and pertussis, and use of antibiotics to limit the destructiveness of bacterial pneumonias, bronchiectasis has become rare. Cystic fibrosis now accounts for about half of cases. As happens in other disease categories when the nongenetic causes are eliminated, the genetic causes become more evident. These include, in addition to CF, the immotile cilia syndrome(s), hereditary bronchomalacia, and immunodeficiencies (Davis et al., 1983), but familial bronchiectasis, in which the nature of the gene-determined defect is unclear, may remain.
Sheridan et al. (2005) studied 2 patients who had elevated sweat chloride (greater than 60 mmol/l) and a history of multiple pulmonary infections, and who carried mutations in the SCNN1B gene. One patient was a 23-year-old African American woman who had sinusitis and mild lung disease, with a forced expiratory volume in 1 second (FEV1) that was 73% of predicted and sputum cultures positive for Pseudomona aeruginosa and Staphylococcus aureus. The other patient was a 7-year-old Caucasian boy who had an FEV1 that was 24% of predicted and sputum cultures positive for Pseudomonas fluorescens at 4 years of age and for Haemophilus parainfluenza at 5 years of age. Both patients had normal pancreatic exocrine function and normal salivary, serum, and urine electrolytes; the boy had an episode of hyponatremic dehydration with elevated aldosterone and renin at 6 months of age, but at the time of study, both patients had normal serum aldosterone and renin activity and normal blood pressure. The female patient was fertile, and vas deferens was present in the boy.
The transmission pattern of BESC1 in the families reported by Sheridan et al. (2005) was consistent with autosomal recessive inheritance.
Sheridan et al. (2005) sequenced the genes encoding the 3 subunits of the epithelial sodium channel (ENaC), SCNN1A (600228), SCNN1B (600760), and SCNN1G (600761), in 20 patients with 'nonclassic' cystic fibrosis without mutations in the CFTR gene, and identified compound heterozygosity for mutations in the SCNN1B gene in 2 patients with elevated sweat chloride and pulmonary disease (600760.0009-600760.0012, respectively).
Fajac et al. (2008) screened the SCNN1B gene in 55 patients with idiopathic bronchiectasis who had 1 or no CFTR mutations and identified heterozygosity for 3 missense mutations in SCNN1B in 5 patients, 2 of whom carried no CFTR mutation (600760.0013-600760.0015, respectively). Fajac et al. (2008) concluded that variants in the SCNN1B gene may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene.
Mutesa et al. (2009) analyzed the CFTR gene in 60 unrelated Rwandan children who had CF-like symptoms and identified heterozygosity for a CFTR mutation in 5 patients (none were homozygous). Analysis of the 3 ENaC genes in these 5 patients revealed heterozygous mutations in SCNN1A and SCNN1B in 4 patients, respectively, whereas the remaining patient was heterozygous for a mutation in both SCNN2B and SCNN1G. Among the patients who were negative for mutation in CFTR, only known polymorphisms were found in the ENaC genes. Mutesa et al. (2009) concluded that some cases of CF-like syndrome in Africa may be associated with mutations in CFTR and ENaC genes.
Genetic Heterogeneity
In a cohort of 55 adult patients with bronchiectasis of unknown etiology, Casals et al. (2004) performed analysis of the CFTR gene (602421), which is mutant in classic cystic fibrosis (219700). The results suggested the involvement of the CFTR gene in patients with bronchiectasis of unknown etiology.
Casals, T., De-Gracia, J., Gallego, M., Dorca, J., Rodriguez-Sanchon, B., Ramos, M. D., Gimenez, J., Cistero-Bahima, A., Olveira, C., Estivill, X. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations? Clin. Genet. 65: 490-495, 2004. [PubMed: 15151509] [Full Text: https://doi.org/10.1111/j.0009-9163.2004.00265.x]
Danielson, G. K., Hanson, C. W., Cooper, E. C. Middle lobe bronchiectasis: report of an unusual familial occurrence. JAMA 201: 605-608, 1967. [PubMed: 5006763] [Full Text: https://doi.org/10.1001/jama.201.8.605]
Davis, P. B., Hubbard, V. S., McCoy, K., Taussig, L. M. Familial bronchiectasis. J. Pediat. 102: 177-185, 1983. [PubMed: 6822919] [Full Text: https://doi.org/10.1016/s0022-3476(83)80515-0]
Fajac, I., Viel, M., Sublemontier, S., Hubert, D., Bienvenu, T. Could a defective epithelial sodium channel lead to bronchiectasis. Respir. Res. 9: 46, 2008. Note: Electronic Article. [PubMed: 18507830] [Full Text: https://doi.org/10.1186/1465-9921-9-46]
Hoo, J. J. Familial middle lobe bronchiectasis. Clin. Genet. 15: 85-88, 1979. [PubMed: 759057] [Full Text: https://doi.org/10.1111/j.1399-0004.1979.tb02031.x]
Mutesa, L., Azad, A. K., Verhaeghe, C., Segers, K., Vanbellinghen, J.-F., Ngendahayo, L., Rusingiza, E. K., Mutwa, P. R., Rulisa, S., Koulischer, L., Cassiman, J.-J., Cuppens, H., Bours, V. Genetic analysis of Rwandan patients with cystic fibrosis-like symptoms: Identification of novel cystic fibrosis transmembrane conductance and epithelial sodium channel gene variants. Chest 135: 1233-1242, 2009. [PubMed: 19017867] [Full Text: https://doi.org/10.1378/chest.08-2246]
Sheridan, M. B., Fong, P., Groman, J. D., Conrad, C., Flume, P., Diaz, R., Harris, C., Knowles, M., Cutting, G. R. Mutations in the beta-subunit of the epithelial Na(+) channel in patients with a cystic fibrosis-like syndrome. Hum. Molec. Genet. 14: 3493-3498, 2005. [PubMed: 16207733] [Full Text: https://doi.org/10.1093/hmg/ddi374]