Document Detail


Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing.
MedLine Citation:
PMID:  16188589     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1). OBJECTIVES: Because CPVT and concealed long QT syndrome (LQTS) phenotypically mimic one other, we sought to determine the spectrum and prevalence of RyR2 mutations in a cohort of unrelated patients who were referred specifically for LQTS genetic testing. METHODS: Using denaturing high-performance liquid chromatography and direct DNA sequencing, targeted mutational analysis of 23 RyR2 exons previously implicated in CPVT1 was performed on genomic DNA from 269 unrelated patients (180 females, average age at diagnosis 24 +/- 17 years) who were referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing. Previously, comprehensive mutational analysis of the five LQTS-associated cardiac channel genes proved negative for this entire subset of patients now designated as "genotype-negative" LQTS referrals. RESULTS: Fifteen distinct RyR2 mutations (14 missense, 1 duplication/insertion, 12 novel) were found in 17 (6.3%) of 269 patients. None of these mutations were present in 400 reference alleles. Two mutations localized to the calstabin-2 (FKBP12.6) binding domain. Upon review of the clinical records, the referral diagnosis for all 17 patients was "atypical" or "borderline" LQTS. CONCLUSION: Putative pathogenic CPVT1-causing mutations in RyR2 were detected in 6% of unrelated, genotype-negative LQTS referrals. These findings suggest that CPVT may be underrecognized among physicians referring patients because of a suspected channelopathy. A diagnosis of "atypical LQTS" may warrant consideration of CPVT and analysis of RyR2 if the standard cardiac channel gene screen for LQTS is negative.
Authors:
David J Tester; Laura J Kopplin; Melissa L Will; Michael J Ackerman
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Heart rhythm : the official journal of the Heart Rhythm Society     Volume:  2     ISSN:  1547-5271     ISO Abbreviation:  Heart Rhythm     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-09-28     Completed Date:  2006-02-13     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101200317     Medline TA:  Heart Rhythm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1099-105     Citation Subset:  IM    
Affiliation:
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Alleles
Child
Cohort Studies
Death, Sudden, Cardiac / etiology
Exercise Test
Family Health
Female
Gene Frequency
Genetic Predisposition to Disease / genetics
Genetic Testing*
Genotype
Humans
Long QT Syndrome / diagnosis,  genetics*,  physiopathology
Male
Middle Aged
Mutation, Missense / genetics*
Myocardial Contraction / physiology
Phenotype
Polymorphism, Genetic / genetics
Referral and Consultation
Ryanodine Receptor Calcium Release Channel / genetics*
Tachycardia, Ventricular / genetics,  physiopathology
Ventricular Fibrillation / genetics,  physiopathology
Grant Support
ID/Acronym/Agency:
HD42569/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Ryanodine Receptor Calcium Release Channel
Comments/Corrections
Comment In:
Heart Rhythm. 2005 Oct;2(10):1106-7   [PMID:  16188590 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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