Risk of syncope in family members who are genotype-negative for a family-associated Long-QT syndrome mutation

Alon Barsheshet, Arthur J. Moss, Scott McNitt, Slava Polonsky, Coeli M. Lopes, Wojciech Zareba, Jennifer L. Robinson, Michael J. Ackerman, Jesaia Benhorin, Elizabeth S. Kaufman, Jeffrey Towbin, G. Michael Vincent, Ming Qi, Ilan Goldenberg

Research output: Contribution to journalArticle

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Abstract

Background-Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families. Methods and Results-Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402-442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P=0.002), prolonged QTc (HR=1.63 per 100 ms increment, P=0.02), family history of ACA or SCD (HR=1.89, P=0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P=0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (P=0.001) increase in the risk of recurrent syncope in genotype-negative subjects. Conclusions-Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.

Original languageEnglish (US)
Pages (from-to)491-499
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume4
Issue number5
DOIs
StatePublished - Oct 1 2011

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Long QT Syndrome
Syncope
Genotype
Mutation
Sudden Cardiac Death
Heart Arrest
Sex Ratio
Genetic Testing
Proportional Hazards Models
Genes
Registries
Parturition
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

Risk of syncope in family members who are genotype-negative for a family-associated Long-QT syndrome mutation. / Barsheshet, Alon; Moss, Arthur J.; McNitt, Scott; Polonsky, Slava; Lopes, Coeli M.; Zareba, Wojciech; Robinson, Jennifer L.; Ackerman, Michael J.; Benhorin, Jesaia; Kaufman, Elizabeth S.; Towbin, Jeffrey; Vincent, G. Michael; Qi, Ming; Goldenberg, Ilan.

In: Circulation: Cardiovascular Genetics, Vol. 4, No. 5, 01.10.2011, p. 491-499.

Research output: Contribution to journalArticle

Barsheshet, A, Moss, AJ, McNitt, S, Polonsky, S, Lopes, CM, Zareba, W, Robinson, JL, Ackerman, MJ, Benhorin, J, Kaufman, ES, Towbin, J, Vincent, GM, Qi, M & Goldenberg, I 2011, 'Risk of syncope in family members who are genotype-negative for a family-associated Long-QT syndrome mutation', Circulation: Cardiovascular Genetics, vol. 4, no. 5, pp. 491-499. https://doi.org/10.1161/CIRCGENETICS.111.960179
Barsheshet, Alon ; Moss, Arthur J. ; McNitt, Scott ; Polonsky, Slava ; Lopes, Coeli M. ; Zareba, Wojciech ; Robinson, Jennifer L. ; Ackerman, Michael J. ; Benhorin, Jesaia ; Kaufman, Elizabeth S. ; Towbin, Jeffrey ; Vincent, G. Michael ; Qi, Ming ; Goldenberg, Ilan. / Risk of syncope in family members who are genotype-negative for a family-associated Long-QT syndrome mutation. In: Circulation: Cardiovascular Genetics. 2011 ; Vol. 4, No. 5. pp. 491-499.
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abstract = "Background-Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families. Methods and Results-Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402-442 ms). The cumulative probability of a first syncope through age 40 years was 15{\%}. However, only 2 patients (0.1{\%}) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P=0.002), prolonged QTc (HR=1.63 per 100 ms increment, P=0.02), family history of ACA or SCD (HR=1.89, P=0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P=0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (P=0.001) increase in the risk of recurrent syncope in genotype-negative subjects. Conclusions-Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.",
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AU - Barsheshet, Alon

AU - Moss, Arthur J.

AU - McNitt, Scott

AU - Polonsky, Slava

AU - Lopes, Coeli M.

AU - Zareba, Wojciech

AU - Robinson, Jennifer L.

AU - Ackerman, Michael J.

AU - Benhorin, Jesaia

AU - Kaufman, Elizabeth S.

AU - Towbin, Jeffrey

AU - Vincent, G. Michael

AU - Qi, Ming

AU - Goldenberg, Ilan

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N2 - Background-Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families. Methods and Results-Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402-442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P=0.002), prolonged QTc (HR=1.63 per 100 ms increment, P=0.02), family history of ACA or SCD (HR=1.89, P=0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P=0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (P=0.001) increase in the risk of recurrent syncope in genotype-negative subjects. Conclusions-Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.

AB - Background-Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families. Methods and Results-Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402-442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P=0.002), prolonged QTc (HR=1.63 per 100 ms increment, P=0.02), family history of ACA or SCD (HR=1.89, P=0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P=0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (P=0.001) increase in the risk of recurrent syncope in genotype-negative subjects. Conclusions-Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.

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