title: Extensive sequence analysis of CFTR, SCNN1A, SCNN1B, SCNN1G and SERPINA1 suggests an oligogenic basis for cystic fibrosis-like phenotypes.
abstract: 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.
authors.affiliation: Center for Molecular Genetic Diagnosis, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: M D
authors.initials: MD
authors.lastname: Ramos
authors.forename: D
authors.initials: D
authors.lastname: Trujillano
authors.forename: R
authors.initials: R
authors.lastname: Olivar
authors.forename: F
authors.initials: F
authors.lastname: Sotillo
authors.forename: S
authors.initials: S
authors.lastname: Ossowski
authors.forename: J
authors.initials: J
authors.lastname: Manzanares
authors.forename: J
authors.initials: J
authors.lastname: Costa
authors.forename: S
authors.initials: S
authors.lastname: Gartner
authors.forename: C
authors.initials: C
authors.lastname: Oliva
authors.forename: E
authors.initials: E
authors.lastname: Quintana
authors.forename: M I
authors.initials: MI
authors.lastname: Gonzalez
authors.forename: C
authors.initials: C
authors.lastname: Vazquez
authors.forename: X
authors.initials: X
authors.lastname: Estivill
authors.forename: T
authors.initials: T
authors.lastname: Casals
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D053503:Epithelial Sodium Channels / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020412:Multifactorial Inheritance / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: C505032:CFTR protein, human; D053503:Epithelial Sodium Channels; C507045:SCNN1A protein, human; C507048:SCNN1B protein, human; C507052:SCNN1G protein, human; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CF-like disease; CFTR; ENaC subunits; SERPINA1; cystic fibrosis