Paralogous annotation of disease-causing variants in long QT syndrome genes.

Human Mutation
James S WareStuart A Cook

Abstract

Discriminating between rare benign and pathogenic variation is a key challenge in clinical genetics, particularly as increasing numbers of nonsynonymous single-nucleotide polymorphisms (SNPs) are identified in resequencing studies. Here, we describe an approach for the functional annotation of nonsynonymous variants that identifies functionally important, disease-causing residues across protein families using multiple sequence alignment. We applied the methodology to long QT syndrome (LQT) genes, which cause sudden death, and their paralogues, which largely cause neurological disease. This approach accurately classified known LQT disease-causing variants (positive predictive value = 98.4%) with a better performance than established bioinformatic methods. The analysis also identified 1078 new putative disease loci, which we incorporated along with known variants into a comprehensive and freely accessible long QT resource (http://cardiodb.org/Paralogue_Annotation/), based on newly created Locus Reference Genomic sequences (http://www.lrg-sequence.org/). We propose that paralogous annotation is widely applicable for Mendelian human disease genes.

References

Oct 5, 1990·Journal of Molecular Biology·S F AltschulD J Lipman
Jan 11, 2000·Nucleic Acids Research·S T SherryK Sirotkin
May 20, 2003·Human Mutation·Peter D StensonDavid N Cooper
Mar 25, 2006·Nucleic Acids Research·Iain M WallaceCedric Notredame
Oct 29, 2009·Human Mutation·Paula L HedleyMichael Christiansen
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Apr 14, 2010·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Oscar CampuzanoRamon Brugada
Apr 20, 2010·Genome Medicine·Raymond DalgleishDonna R Maglott
Jun 22, 2010·American Journal of Human Genetics·Yanzong YangYi-Han Chen
Nov 23, 2010·Nucleic Acids Research·Joanna L SharmanUNKNOWN NC-IUPHAR
Aug 4, 2011·Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology·Michael J AckermanUNKNOWN European Heart Rhythm Association (EHRA)
Aug 19, 2011·Nature Reviews. Genetics·Gregory M Cooper, Jay Shendure

❮ Previous
Next ❯

Citations

Dec 11, 2013·Nature Reviews. Cardiology·Roos F MarsmanConnie R Bezzina
Feb 15, 2013·Journal of the American Medical Informatics Association : JAMIA·Zhe ZhangEmil Alexov
Feb 3, 2016·Frontiers in Pharmacology·Gildas LoussouarnFlavien Charpentier
Nov 29, 2013·Nucleic Acids Research·Jacqueline A L MacArthurFiona Cunningham
Dec 4, 2013·Nucleic Acids Research·Sungsam GongStuart A Cook
Apr 10, 2015·Journal of Cardiovascular Translational Research·Jamie D KapplingerMichael J Ackerman
Jun 16, 2016·Frontiers in Cardiovascular Medicine·Najim LahrouchiConnie R Bezzina
Jan 26, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Nicola WhiffinStuart A Cook
Dec 25, 2019·Genome Research·Eduardo Pérez-PalmaDennis Lal
Aug 18, 2020·Science Translational Medicine·Henrike O HeyneMark J Daly
Feb 9, 2021·Molecular Genetics and Metabolism Reports·Dulce QuelhasEsmeralda Martins
Nov 5, 2019·Biochemical and Biophysical Research Communications·Svetlana I TarnovskayaDmitrij Frishman

❮ Previous
Next ❯

Related Concepts

Related Feeds

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.