Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment |
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| Institution: | 1. Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States;2. Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States;3. Department of Genome Sciences, University of Washington, Seattle, WA 98195, United States;4. Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, United States;5. Department of Pediatrics, University of Washington, Seattle, WA 98195, United States;6. Brotman-Baty Institute, Seattle, WA 98195, United States;7. Division of Pediatric Endocrinology and Diabetes, Johns Hopkins University, Baltimore, MD 21287, United States;1. Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA;2. Department of Respirology, St Michael''s Hospital, University of Toronto, Toronto, Ontario, Canada;3. Department of Pediatrics, University of Washington, Seattle, WA, USA;4. Seattle Children''s Research Institute, Seattle, WA, USA;1. Louvain Center for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique;2. Cystic Fibrosis Center, Belgium;3. Medicinal Chemistry Research Lab, Louvain Drug Research Institute;4. Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute;5. Université catholique de Louvain (UCLouvain), Brussels, Belgium;6. Katholieke Universiteit Leuven (UZLeuven), Leuven, Belgium;1. Division of Thoracic Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States;2. Department of Medicine, Pulmonary, Allergy, and Critical Care Medicine Division, University of Pittsburgh, Pittsburgh, PA, United States;1. Cardiff and Vale University Health Board, Wales, United Kingdom;2. Cardiff University, Wales, United Kingdom;1. Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany;2. Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 130.3, D-69120 Heidelberg, Germany;3. Department of Pediatric Pulmonology, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charite -Universitätsmedizin Berlin, Berlin, Germany;4. Division of Neuropediatrics and Metabolic Medicine and Newborn Screening Center, Department of Paediatrics I, Center for Pediatric and Adolescent Medicine University Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany;5. Berlin Institute of Health (BIH), Berlin, Germany;6. German Center for Lung Research (DZL), associated partner site, Berlin, Germany |
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| Abstract: | BackgroundCystic fibrosis (CF) is a recessive condition caused by variants in each CF transmembrane conductance regulator (CFTR) allele. Clinically affected individuals without two identified causal variants typically have no further interrogation of CFTR beyond examination of coding regions, but the development of variant-specific CFTR-targeted treatments necessitates complete understanding of CFTR genotype.MethodsWhole genome sequences were analyzed on 5,058 individuals with CF. We focused on the full CFTR gene sequence and identified disease-causing variants in three phases: screening for known and structural variants; discovery of novel loss-of-function variants; and investigation of remaining variants.ResultsAll variants identified in the first two phases and coding region variants found in the third phase were interpreted according to CFTR2 or ACMG criteria (n = 371; 16 4.3%] previously unreported). Full gene sequencing enabled delineation of 18 structural variants (large insertions or deletions), of which two were novel. Additional CFTR variants of uncertain effect were found in 76 F508del homozygotes and in 21 individuals with other combinations of CF-causing variants. Both causative variants were identified in 98.1% (n = 4,960) of subjects, an increase of 2.3 percentage points from the 95.8% (n = 4,847) who had a registry- or chart-reported disease-causing CFTR genotype. Of the remaining 98 individuals, 78 carried one variant that has been associated with CF (CF-causing n = 70] or resulting in varying clinical consequences n = 8]).ConclusionsComplete CFTR gene sequencing in 5,058 individuals with CF identified at least one DNA variant in 99.6% of the cohort that is targetable by current molecular or emerging gene-based therapeutic technologies. |
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