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Exome analysis of a family with Wolff–Parkinson–White syndrome identifies a novel disease locus
Author(s) -
Bowles Neil E.,
Jou Chuanchau J.,
Arrington Cammon B.,
Kennedy Brett J.,
Earl Aubree,
Matsunami Norisada,
Meyers Lindsay L.,
Etheridge Susan P.,
Saarel Elizabeth V.,
Bleyl Steven B.,
Yost H. Joseph,
Yandell Mark,
Leppert Mark F.,
TristaniFirouzi Martin,
Gruber Peter J.
Publication year - 2015
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.37297
Subject(s) - exome sequencing , genetics , medicine , phenotype , exome , locus (genetics) , gene , biology
Wolff–Parkinson–White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2 , which encodes the 5′‐AMP‐activated protein kinase subunit γ‐2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology‐based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6 . MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. © 2015 Wiley Periodicals, Inc.