Extensive sequence analysis of CFTR, SCNN1A, SCNN1B, SCNN1G and SERPINA1 suggests an oligogenic basis for cystic fibrosis-like phenotypes

• Published in: Clinical genetics Vol. 86; no. 1; pp. 91 - 95
• Main Authors: Ramos, M.D., Trujillano, D., Olivar, R., Sotillo, F., Ossowski, S., Manzanares, J., Costa, J., Gartner, S., Oliva, C., Quintana, E., Gonzalez, M.I., Vazquez, C., Estivill, X., Casals, T.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2014
• Subjects: Adolescent; Adult; alpha 1-Antitrypsin - genetics; Base Sequence; CF-like disease; CFTR; Child; Cystic fibrosis; Cystic Fibrosis - genetics; Cystic Fibrosis - pathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; ENaC subunits; Epithelial Sodium Channels - genetics; Exome - genetics; Female; Genomics; Genotype & phenotype; Humans; Male; Molecular Sequence Data; Multifactorial Inheritance - genetics; Mutation; Pedigree; Phenotype; Sequence Analysis, DNA; SERPINA1; ENaC subunits; SERPINA1; CF-like disease; cystic fibrosis; CFTR
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.12234

The term cystic fibrosis (CF)‐like disease is used to describe patients with a borderline sweat test and suggestive CF clinical features but without two CFTR(cystic fibrosis transmembrane conductance regulator) mutations. We have performed the extensive molecular analysis of four candidate genes (SCNN1A, SCNN1B, SCNN1G and SERPINA1) in a cohort of 10 uncharacterized patients with CF and CF‐like disease. We have used whole‐exome sequencing to characterize mutations in the CFTR gene and these four candidate genes. CFTR molecular analysis allowed a complete characterization of three of four CF patients. Candidate variants in SCNN1A, SCNN1B, SCNN1G and SERPINA1 in six patients with CF‐like phenotypes were confirmed by Sanger sequencing and were further supported by in silico predictive analysis, pedigree studies, sweat test in other family members, and analysis in CF patients and healthy subjects. Our results suggest that CF‐like disease probably results from complex genotypes in several genes in an oligogenic form, with rare variants interacting with environmental factors.