In this section
@article{Walsh:2013:10.1136/jmedgenet-2013-101917,
author = {Walsh, R and Peters, NS and Cook, SA and Ware, JS},
doi = {10.1136/jmedgenet-2013-101917},
journal = {Journal of Medical Genetics},
pages = {35--44},
title = {Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia},
url = {http://dx.doi.org/10.1136/jmedgenet-2013-101917},
volume = {51},
year = {2013}
}
TY - JOUR
AB - Background Distinguishing genetic variants that causedisease from variants that are rare but benign is one ofthe principal challenges in contemporary clinicalgenetics, particularly as variants are identified at a paceexceeding the capacity of researchers to characterisethem functionally.Methods We previously developed a novel method,called paralogue annotation, which accurately andspecifically identifies disease-causing missense variants bytransferring disease-causing annotations across families ofrelated proteins. Here we refine our approach, and applyit to novel variants found in 2266 patients across twolarge cohorts with inherited sudden death syndromes,namely catecholaminergic polymorphic ventriculartachycardia (CPVT) or Brugada syndrome (BrS).Results Over one third of the novel non-synonymousvariants found in these studies, which would otherwisebe reported in a clinical diagnostics setting as ‘variants ofunknown significance’, are categorised by our method aslikely disease causing (positive predictive value 98.7%).This identified more than 500 new disease loci for BrSand CPVT.Conclusions Our methodology is widely transferableacross all human disease genes, with an estimated150 000 potentially informative annotations in more than1800 genes. We have developed a web resource thatallows researchers and clinicians to annotate variantsfound in individuals with inherited arrhythmias,comprising a referenced compendium of known missensevariants in these genes together with a user-friendlyimplementation of our approach. This tool will facilitatethe interpretation of many novel variants that mightotherwise remain unclassified.
AU - Walsh,R
AU - Peters,NS
AU - Cook,SA
AU - Ware,JS
DO - 10.1136/jmedgenet-2013-101917
EP - 44
PY - 2013///
SN - 1468-6244
SP - 35
TI - Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia
T2 - Journal of Medical Genetics
UR - http://dx.doi.org/10.1136/jmedgenet-2013-101917
UR - http://hdl.handle.net/10044/1/24490
VL - 51
ER -