Exome analysis of a family with Wolff-Parkinson-White syndrome identifies a novel disease locus.
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.
Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah.
Neil E
NE
Bowles
Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah.|Nora Eccles Cardiovascular Research and Training Institute, Salt Lake City, Utah.
Chuanchau J
CJ
Jou
Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah.
Cammon B
CB
Arrington
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah.
Brett J
BJ
Kennedy
Department of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, Utah.
Aubree
A
Earl
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah.
Norisada
N
Matsunami
Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah.
Lindsay L
LL
Meyers
Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah.
Susan P
SP
Etheridge
Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah.
Elizabeth V
EV
Saarel
Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah.|Clinical Genetics Institute, Intermountain Healthcare, Salt Lake City, Utah.
Steven B
SB
Bleyl
Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah.
H Joseph
HJ
Yost
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah.|USTAR Center for Genetic Discovery, University of Iowa, Iowa City, Iowa.
Mark
M
Yandell
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah.
Mark F
MF
Leppert
Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah.|Nora Eccles Cardiovascular Research and Training Institute, Salt Lake City, Utah.
Martin
M
Tristani-Firouzi
Department of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, Utah.|Department of Cardiothoracic Surgery, University of Iowa, Iowa City, Iowa.
Peter J
PJ
Gruber
D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000328:Adult; D024722:Cardiac Myosins / Q000235:genetics; D059472:Exome; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D018995:Myosin Heavy Chains / Q000235:genetics; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D014927:Wolff-Parkinson-White Syndrome / Q000209:etiology / Q000235:genetics*
C489619:KCNE2 protein, human; C094239:MYH6 protein, human; D024642:Potassium Channels, Voltage-Gated; C526223:PRKAG2 protein, human; D055372:AMP-Activated Protein Kinases; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
MYH6; Wolff-Parkinson-White; whole exome sequencing