title: Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.
abstract: Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of ł0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.
authors: 1] Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. [2] Perdana University Graduate School of Medicine, Serdang, Malaysia. [3] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Patrick R
authors: PR
authors: Sosnay
authors: Karen R
authors: KR
authors: Siklosi
authors: Fredrick
authors: F
authors: Van Goor
authors: Kyle
authors: K
authors: Kaniecki
authors: Haihui
authors: H
authors: Yu
authors: Neeraj
authors: N
authors: Sharma
authors: Anabela S
authors: AS
authors: Ramalho
authors: Margarida D
authors: MD
authors: Amaral
authors: Ruslan
authors: R
authors: Dorfman
authors: Julian
authors: J
authors: Zielenski
authors: David L
authors: DL
authors: Masica
authors: Rachel
authors: R
authors: Karchin
authors: Linda
authors: L
authors: Millen
authors: Philip J
authors: PJ
authors: Thomas
authors: George P
authors: GP
authors: Patrinos
authors: Mary
authors: M
authors: Corey
authors: Michelle H
authors: MH
authors: Lewis
authors: Johanna M
authors: JM
authors: Rommens
authors: Carlo
authors: C
authors: Castellani
authors: Christopher M
authors: CM
authors: Penland
authors: Garry R
authors: GR
authors: Cutting
mesh_terms: D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
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