Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene
By P. Sosnay, K. R. Siklosi, F. van Goor, Kyle Kaniecki, Haihui Yu, N. Sharma, A. Ramalho, M. Amaral, R. Dorfman, J. Zieleński and 11 more. Nature Genetics, 2013
604 citations recorded by the source corpus.
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.
Subfields: Cognitive Neuroscience, Psychiatry and Mental health, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/789d766eb8218cf6e6337c7740aee90f9c932eaf
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Citations in the corpus
- Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (2015, methodology): “Gorlin syndrome including basal cell carcinoma, palmoplantar pits, odontogenic keratocysts); (3) the gene is not subject to substantial benign variation which can be determined through large general population cohorts (e.”