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. Penland & 1 others Garry R. Cutting

Research output: Contribution to journalArticle

285 Citations (Scopus)

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 2013

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Regulator Genes
Cystic Fibrosis
Aptitude
Penetrance
North America
Gene Frequency
Fathers
Registries
Genotype
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Sosnay, P. R., Siklosi, K. R., Van Goor, F., Kaniecki, K., Yu, H., Sharma, N., ... Cutting, G. R. (2013). Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nature Genetics, 45(10), 1160-1167. https://doi.org/10.1038/ng.2745

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. / Sosnay, Patrick R.; Siklosi, Karen R.; Van Goor, Fredrick; Kaniecki, Kyle; Yu, Haihui; Sharma, Neeraj; Ramalho, Anabela S.; Amaral, Margarida D.; Dorfman, Ruslan; Zielenski, Julian; Masica, David L.; Karchin, Rachel; Millen, Linda; Thomas, Philip J.; Patrinos, George P.; Corey, Mary; Lewis, Michelle H.; Rommens, Johanna M.; Castellani, Carlo; Penland, Christopher M.; Cutting, Garry R.

In: Nature Genetics, Vol. 45, No. 10, 10.2013, p. 1160-1167.

Research output: Contribution to journalArticle

Sosnay, PR, Siklosi, KR, Van Goor, F, Kaniecki, K, Yu, H, Sharma, N, Ramalho, AS, Amaral, MD, Dorfman, R, Zielenski, J, Masica, DL, Karchin, R, Millen, L, Thomas, PJ, Patrinos, GP, Corey, M, Lewis, MH, Rommens, JM, Castellani, C, Penland, CM & Cutting, GR 2013, 'Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene', Nature Genetics, vol. 45, no. 10, pp. 1160-1167. https://doi.org/10.1038/ng.2745
Sosnay, Patrick R. ; Siklosi, Karen R. ; Van Goor, Fredrick ; Kaniecki, Kyle ; Yu, Haihui ; Sharma, Neeraj ; Ramalho, Anabela S. ; Amaral, Margarida D. ; Dorfman, Ruslan ; Zielenski, Julian ; Masica, David L. ; Karchin, Rachel ; Millen, Linda ; Thomas, Philip J. ; Patrinos, George P. ; Corey, Mary ; Lewis, Michelle H. ; Rommens, Johanna M. ; Castellani, Carlo ; Penland, Christopher M. ; Cutting, Garry R. / Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. In: Nature Genetics. 2013 ; Vol. 45, No. 10. pp. 1160-1167.
@article{cfa14bda83f74ad79a8df540e2e4fe0e,
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.",
author = "Sosnay, {Patrick R.} and Siklosi, {Karen R.} and {Van Goor}, Fredrick and Kyle Kaniecki and Haihui Yu and Neeraj Sharma and Ramalho, {Anabela S.} and Amaral, {Margarida D.} and Ruslan Dorfman and Julian Zielenski and Masica, {David L.} and Rachel Karchin and Linda Millen and Thomas, {Philip J.} and Patrinos, {George P.} and Mary Corey and Lewis, {Michelle H.} and Rommens, {Johanna M.} and Carlo Castellani and Penland, {Christopher M.} and Cutting, {Garry R.}",
year = "2013",
month = "10",
doi = "10.1038/ng.2745",
language = "English (US)",
volume = "45",
pages = "1160--1167",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

AU - Sosnay, Patrick R.

AU - Siklosi, Karen R.

AU - Van Goor, Fredrick

AU - Kaniecki, Kyle

AU - Yu, Haihui

AU - Sharma, Neeraj

AU - Ramalho, Anabela S.

AU - Amaral, Margarida D.

AU - Dorfman, Ruslan

AU - Zielenski, Julian

AU - Masica, David L.

AU - Karchin, Rachel

AU - Millen, Linda

AU - Thomas, Philip J.

AU - Patrinos, George P.

AU - Corey, Mary

AU - Lewis, Michelle H.

AU - Rommens, Johanna M.

AU - Castellani, Carlo

AU - Penland, Christopher M.

AU - Cutting, Garry R.

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84885022205&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885022205&partnerID=8YFLogxK

U2 - 10.1038/ng.2745

DO - 10.1038/ng.2745

M3 - Article

VL - 45

SP - 1160

EP - 1167

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 10

ER -