TY - JOUR
T1 - Loss-of-Function KCNE2 Variants
T2 - True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?
AU - Roberts, Jason D.
AU - Krahn, Andrew D.
AU - Ackerman, Michael J.
AU - Rohatgi, Ram K.
AU - Moss, Arthur J.
AU - Nazer, Babak
AU - Tadros, Rafik
AU - Gerull, Brenda
AU - Sanatani, Shubhayan
AU - Wijeyeratne, Yanushi D.
AU - Baruteau, Alban Elouen
AU - Muir, Alison R.
AU - Pang, Benjamin
AU - Cadrin-Tourigny, Julia
AU - Talajic, Mario
AU - Rivard, Lena
AU - Tester, David J.
AU - Liu, Taylor
AU - Whitman, Isaac R.
AU - Wojciak, Julianne
AU - Conacher, Susan
AU - Gula, Lorne J.
AU - Leong-Sit, Peter
AU - Manlucu, Jaimie
AU - Green, Martin S.
AU - Hamilton, Robert
AU - Healey, Jeff S.
AU - Lopes, Coeli M.
AU - Behr, Elijah R.
AU - Wilde, Arthur A.
AU - Gollob, Michael H.
AU - Scheinman, Melvin M.
N1 - Funding Information:
Dr Roberts is supported by the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network (C-SPIN), and the Cardiac Arrhythmia Network of Canada (CANet). Dr Krahn receives support from the Heart and Stroke Foundation of Canada, the Sauder Family and Heart and Stroke Foundation Chair in Cardiology, and the Paul Brunes Chair in Heart Rhythm Disorders. The study was supported by the Heart and Stroke Foundation of Canada (G-13-0002775 and G-14-0005732), the Canadian Institutes of Health Research (343256; Canadian Long QT Registry), the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (Dr Ackerman), and research grants HL-33843, HL-51618, and HL-123483 from the National Institutes of Health, Bethesda, MD (Dr Moss).
Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Methods and Results - Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the KCNE2 variant was not the underlying culprit. The collective frequency of KCNE2 variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6. Conclusions - On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.
AB - Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Methods and Results - Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the KCNE2 variant was not the underlying culprit. The collective frequency of KCNE2 variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6. Conclusions - On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.
KW - exome
KW - genetics
KW - long QT syndrome
KW - mutation
KW - prevalence
UR - http://www.scopus.com/inward/record.url?scp=85028868563&partnerID=8YFLogxK
U2 - 10.1161/CIRCEP.117.005282
DO - 10.1161/CIRCEP.117.005282
M3 - Article
C2 - 28794082
AN - SCOPUS:85028868563
SN - 1941-3149
VL - 10
JO - Circulation: Arrhythmia and Electrophysiology
JF - Circulation: Arrhythmia and Electrophysiology
IS - 8
M1 - e005282
ER -