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The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome
  1. I M Van Langen1,
  2. E Birnie2,
  3. M Alders1,
  4. R J Jongbloed3,
  5. H Le Marec4,
  6. A A M Wilde5
  1. 1Department of Clinical Genetics, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
  2. 2Department of Social Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
  3. 3Division of Genetics and Cell Biology, University of Maastricht, Joseph Bechlaan 113, 6229 GR, Maastricht, The Netherlands
  4. 4Clinique Cardiologique, Hôpital G&R Laënnec, CHU de Nantes, 44093 Nantes Cedex, France
  5. 5Experimental and Molecular Cardiology Group, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, and The Netherlands Interuniversity Cardiologic Institute (ICIN), Catharijnesingel 52, 3501 DG Utrecht, The Netherlands
  1. Correspondence to:
 Dr I M van Langen, Department of Clinical Genetics, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands;
 i.m.vanlangen{at}amc.uva.nl

https://doi.org/10.1136/jmg.40.2.141

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    The autosomal dominant form of the congenital long QT syndrome (LQTS or Romano-Ward syndrome) is a disease of disturbance of repolarisation of cardiac myocytes secondary to malfunctioning ion channels, potentially leading to ventricular arrhythmias. The estimated prevalence is 1 in 5000-7000.1

    LQTS is diagnosed by analysis of surface electrocardiograms, clinical presentation, and family history.2 Cardiac events in first and second degree relatives of LQTS patients occur in 6-13% of cases.3 Thirty percent of mutation carriers do not have a prolonged QT interval, but are still at risk for complications.4,5 Beta blockers and adjustments in life style are effective in most LQTS patients.6

    Up to now, five LQTS genes (and one locus on chromosome 4) have been identified: KCNH2, KCNQ1, SCN5A, KCNE1, and KCNE2 on chromosomes 7, 11, 3, 21, and 21, respectively. At present, the genotype has been identified in 50-70% of patients. Most patients have a private (missense) mutation in KCNH2 or KCNQ1.7

    Diagnostic screening of all five LQTS associated genes at once potentially leads to relatively fast mutation detection but is very labour intensive and costly. Sequential mutational analysis, starting with the gene that accounts for the largest percentage of mutations based on published gene prevalences (KCNH2, 45%), has the same disadvantages, albeit to a lesser extent.7 In most patients, a mutation will not be detected at the first attempt, so in most cases at least two genes have to be screened to detect the disease causing mutation. This is a major drawback for diagnosis of mutations in LQTS.8–10 Nevertheless, several commercial diagnostic services exist.11

    Distinct genotype-phenotype correlations have been reported in LQTS. Age of onset, symptom related triggers, the ST-T segment morphology of the ECG, and the response to drugs …

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