Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

Patrick R. Sosnay, Karen R. Siklosi, Fredrick Van Goor, Kyle Kaniecki, Haihui Yu, Neeraj Sharma, Anabela S. Ramalho, Margarida D. Amaral, Ruslan Dorfman, Julian Zielenski, David L. Masica, Rachel Karchin, Linda Millen, Philip J. Thomas, George P. Patrinos, Mary Corey, Michelle H. Lewis, Johanna M. Rommens, Carlo Castellani, Christopher M. PenlandGarry R. Cutting

Research output: Contribution to journalArticlepeer-review

349 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1160-1167
Number of pages8
JournalNature genetics
Volume45
Issue number10
DOIs
StatePublished - Oct 1 2013

ASJC Scopus subject areas

  • Genetics

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