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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Estimating the Posttest Probability of Long QT Syndrome Diagnosis for Rare KCNH2 Variants
Circulation: Genomic and Precision Medicine, Volume 14, No. 4, Year 2021
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Description
Background: The proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. This raises the question of whether these variants can be useful predictors of disease. To answer this question, we assessed the degree to which the presence of a variant in the cardiac potassium channel gene KCNH2 was diagnostically predictive for the autosomal dominant long QT syndrome. Methods: We estimated the probability of a long QT diagnosis given the presence of each KCNH2 variant using Bayesian methods that incorporated variant features such as changes in variant function, protein structure, and in silico predictions. We call this estimate the posttest probability of disease. Our method was applied to over 4000 individuals heterozygous for 871 missense or in-frame insertion/deletion variants in KCNH2 and validated against a separate international cohort of 933 individuals heterozygous for 266 missense or in-frame insertion/deletion variants. Results: Our method was well-calibrated for the observed fraction of heterozygotes diagnosed with long QT syndrome. Heuristically, we found that the innate diagnostic information one learns about a variant from 3-dimensional variant location, in vitro functional data, and in silico predictors is equivalent to the diagnostic information one learns about that same variant by clinically phenotyping 10 heterozygotes. Most importantly, these data can be obtained in the absence of any clinical observations. Conclusions: We show how variant-specific features can inform a prior probability of disease for rare variants even in the absence of clinically phenotyped heterozygotes. © 2021 Lippincott Williams and Wilkins. All rights reserved.
Authors & Co-Authors
Wada, Yuko
United States, Nashville
Vanderbilt University Medical Center
Japan, Otsu
Shiga University of Medical Science
Sala, Luca
Italy, Milan
Irccs Istituto Auxologico Italiano
Denjoy, Isabelle
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Aiba, Takeshi
Japan, Suita
National Cerebral and Cardiovascular Center
Shimizu, Wataru
Japan, Tokyo
Nippon Medical School
Makita, Naomasa
Japan, Suita
National Cerebral and Cardiovascular Center
Ishikawa, Taisuke
Japan, Suita
National Cerebral and Cardiovascular Center
CROTTI, L.
Italy, Milan
Irccs Istituto Auxologico Italiano
Italy, Milan
Università Degli Studi Di Milano-bicocca
Spazzolini, Carla
Italy, Milan
Irccs Istituto Auxologico Italiano
Kotta, Maria Christina
Italy, Milan
Irccs Istituto Auxologico Italiano
Dagradi, Federica
Italy, Milan
Irccs Istituto Auxologico Italiano
Castelletti, Silvia
Italy, Milan
Irccs Istituto Auxologico Italiano
Pedrazzini, Matteo
Italy, Milan
Irccs Istituto Auxologico Italiano
Gnecchi, Massimiliano
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Leenhardt, Antoine R.
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
France, Paris
Université Paris Cité
Salem, Joe Elie
United States, Nashville
Vanderbilt University Medical Center
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Ohno, Seiko
Japan, Otsu
Shiga University of Medical Science
Japan, Suita
National Cerebral and Cardiovascular Center
Mosley, Jonathan D.
United States, Nashville
Vanderbilt University Medical Center
United States, Nashville
Vanderbilt University
Roden, Dan M.L.
United States, Nashville
Vanderbilt University Medical Center
United States, Nashville
Vanderbilt University
Schwartz, Peter J.
Italy, Milan
Irccs Istituto Auxologico Italiano
Horie, Minoru
Japan, Otsu
Shiga University of Medical Science
Statistics
Citations: 7
Authors: 21
Affiliations: 11
Identifiers
Doi:
10.1161/CIRCGEN.120.003289
ISSN:
25748300
Research Areas
Genetics And Genomics
Noncommunicable Diseases
Study Design
Cohort Study