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,Kyle Kaniecki,Haihui Yu,Neeraj Sharma,Anabela S. Ramalho,Anabela S. Ramalho,Margarida D. Amaral,Margarida D. Amaral,Ruslan Dorfman,Julian Zielenski,David L. Masica,Rachel Karchin,Linda Millen,Philip Thomas,George P. Patrinos,Mary Corey,Michelle Huckaby Lewis,Johanna M. Rommens,Carlo Castellani,Christopher M. Penland,Garry R. Cutting +23 more
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TLDR
It is illustrated that sourcing data directly from well-phenotyped subjects can address the gap in the ability to interpret clinically relevant genomic variation in patients with cystic fibrosis.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 l0.01%. 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.read more
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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.
Sue Richards,Nazneen Aziz,Nazneen Aziz,Sherri J. Bale,David P. Bick,Soma Das,Julie M. Gastier-Foster,Wayne W. Grody,Madhuri Hegde,Elaine Lyon,Elaine B. Spector,Karl V. Voelkerding,Heidi L. Rehm +12 more
TL;DR: Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends thatclinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
Journal ArticleDOI
ClinGen — The Clinical Genome Resource
Heidi L. Rehm,Jonathan S. Berg,Lisa D. Brooks,Carlos Bustamante,James P. Evans,Melissa J. Landrum,David H. Ledbetter,Donna Maglott,Christa Lese Martin,Robert L. Nussbaum,Sharon E. Plon,Erin M. Ramos,Stephen T. Sherry,Michael S. Watson +13 more
TL;DR: A patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication, and a different variant is found that is determined to be pathogenic.
Journal ArticleDOI
Cystic fibrosis genetics: from molecular understanding to clinical application
TL;DR: Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.
Journal ArticleDOI
Long-term expanding human airway organoids for disease modeling
Norman Sachs,Angelos Papaspyropoulos,Domenique D. Zomer-van Ommen,Inha Heo,Lena Böttinger,Dymph Klay,Fleur Weeber,Guizela Huelsz-Prince,Nino Iakobachvili,Gimano D. Amatngalim,Joep de Ligt,Arne Van Hoeck,Natalie Proost,Marco C. Viveen,Anna Lyubimova,Luc Teeven,Sepideh Derakhshan,Jeroen Korving,Harry Begthel,Johanna F. Dekkers,Kuldeep Kumawat,Emilio Ramos,Matthijs F.M. van Oosterhout,G. Johan A. Offerhaus,Dominique J Wiener,Eduardo P. Olimpio,Krijn K. Dijkstra,Egbert F. Smit,Maarten van der Linden,Sridevi Jaksani,Marieke van de Ven,Jos Jonkers,Anne C. Rios,Emile E. Voest,Coline H.M. van Moorsel,Cornelis K. van der Ent,Edwin Cuppen,Alexander van Oudenaarden,Frank E. J. Coenjaerts,Linde Meyaard,Louis Bont,Peter J. Peters,Sander J. Tans,Jeroen S. van Zon,Sylvia F. Boj,Robert G.J. Vries,Jeffrey M. Beekman,Hans Clevers +47 more
TL;DR: It is concluded that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.
Journal ArticleDOI
Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation
Philip M. Farrell,Terry B. White,Clement L. Ren,Sarah E. Hempstead,Frank J. Accurso,Nico Derichs,Michelle S. Howenstine,Susanna A. McColley,Michael J. Rock,Margaret Rosenfeld,Isabelle Sermet-Gaudelus,Kevin W Southern,Bruce C. Marshall,Patrick R. Sosnay +13 more
TL;DR: In this article, a consensus committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations.
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A CFTR potentiator in patients with cystic fibrosis and the G551D mutation
Bonnie W. Ramsey,Jane C. Davies,N. Gerard McElvaney,Elizabeth Tullis,Scott C. Bell,Pavel Dř evínek,Matthias Griese,Edward F. McKone,Claire E. Wainwright,Michael W. Konstan,Richard B. Moss,Felix Ratjen,Isabelle Sermet-Gaudelus,Steven M. Rowe,Qunming Dong,Sally Rodriguez,Karl Yen,Claudia L. Ordoñez,J. Stuart Elborn +18 more
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