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

Authors

  • M.D. Ramos,

    1. Center for Molecular Genetic Diagnosis, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
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    • Nothing to declare
  • D. Trujillano,

    1. Genetic Causes of Disease Group, Centre for Genomic Regulation (CRG), Barcelona, Spain
    2. Department of Genetics, Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona, Spain
    3. Centre for Genomic Regulation, Hospital del Mar Research Institute, Barcelona, Spain
    4. Centre for Genomic Regulation, CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain
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    • Nothing to declare
  • R. Olivar,

    1. Human Molecular Genetics Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
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  • F. Sotillo,

    1. Human Molecular Genetics Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
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  • S. Ossowski,

    1. Department of Genetics, Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona, Spain
    2. Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), Barcelona, Spain
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  • J. Manzanares,

    1. Cystic Fibrosis Unit, Hospital 12 de Octubre, Madrid, Spain
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  • J. Costa,

    1. Cystic Fibrosis Unit, Hospital Parc Taulí, Sabadell, Spain
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  • S. Gartner,

    1. Cystic Fibrosis Unit, Hospital Vall d'Hebron, Barcelona, Spain
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  • C. Oliva,

    1. Cystic Fibrosis Unit, Hospital Virgen Candelaria, Tenerife, Spain
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  • E. Quintana,

    1. Cystic Fibrosis Unit, Hospital Virgen del Rocio, Sevilla, Spain
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  • M.I. Gonzalez,

    1. Cystic Fibrosis Unit, Hospital Niño Jesus, Madrid, Spain
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  • C. Vazquez,

    1. Cystic Fibrosis Unit, Hospital de Cruces, Barakaldo, Spain
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  • X. Estivill,

    1. Genetic Causes of Disease Group, Centre for Genomic Regulation (CRG), Barcelona, Spain
    2. Department of Genetics, Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona, Spain
    3. Centre for Genomic Regulation, Hospital del Mar Research Institute, Barcelona, Spain
    4. Centre for Genomic Regulation, CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain
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  • T. Casals

    Corresponding author
    1. Center for Molecular Genetic Diagnosis, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
    2. Human Molecular Genetics Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
    • Corresponding author: Teresa Casals, PhD, Human Molecular Genetics Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Gran Via de l'Hospitalet, 199 08908 Barcelona, Catalonia, Spain.

      Tel.: +3493 260 7425;

      fax: +3493 260 7414;

      e-mail: tcasals@idibell.cat

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  • These authors equally contributed.

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.

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