Long QT syndrome in South Africa : the results of comprehensive genetic screening : cardiovascular topic

Paula L Hedley,Firzana Hendricks,Glenda A Durrheim,Birgitte Stovring,Valerie A Corfield,Cathrine Jespersgaard,Michael Christiansen,Paul A Brink,Althea Goosen,Tam T Pham

doi:10.5830/cvja-2013-032

Paula L Hedley, Firzana Hendricks + Show 8 more

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https://doi.org/10.5830/cvja-2013-032

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Abstract

Congenital long QT syndrome (cLQTS) is a genetic disorder predisposing to ventricular arrhythmia, syncope and sudden death. Over 700 different cLQTS-causing mutations in 13 genes are known. The genetic spectrum of LQTS in 44 South African cLQTS patients (23 known to carry the South African founder mutation p.A341V in KCNQ1) was established by screening for mutations in the coding regions of KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A, the most frequently implicated cLQTS-causing genes (five-gene screening). Fourteen disease-causing mutations were identified, eight (including the founder mutation) in KCNQ1, five in KCNH2 and one in KCNE1. Two mutations were novel. Two double heterozygotes were found among the 23 families (8.5%) carrying the founder mutation. In conclusion, cLQTS in South Africa reflects both a strong founder effect and a genetic spectrum similar to that seen in other populations. Consequently, five-gene screening should be offered as a standard screening option, as is the case internationally. This will disclose compound and double heterozygotes. Fivegene screening will most likely be even more informative in other South African sub-populations with a greater genetic diversity.

Highlights

Congenital long QT syndrome is a genetic disorder predisposing to ventricular arrhythmia, syncope and sudden death
Several clinical syndromes have been described: RomanoWard syndrome (RWS), an autosomal dominant form of Congenital long QT syndrome (cLQTS), which presents clinically with a pure cardiac phenotype; Jervell and Lange-Nielsen syndrome (JLNS), an autosomal recessive form of LQTS which is associated with congenital deafness;[2] Andersen-Tawil syndrome (ATS), which is an autosomal dominant multisystem disorder where cLQTS is variably present; and Timothy syndrome (TS), which is characterised by severe cLQTS as well as cardiac and somatic malformations
Three mutations were identified among the 23 founder probands; all harboured the South African founder mutation KCNQ1:p.A341V, while two probands (8.5%) harboured an additional mutation in a second cLQTS-causing gene, which may contribute to disease

Summary

Introduction

Congenital long QT syndrome (cLQTS) is a genetic disorder predisposing to ventricular arrhythmia, syncope and sudden death. Five-gene screening should be offered as a standard screening option, as is the case internationally This will disclose compound and double heterozygotes. CLQTS provides the archetypical monogenic disorder for studying the genetic basis of inherited arrhythmia syndromes in that it is relatively common (prevalence of 1:2 500 to 1:5 000),[3] and more than 700 disease-causing mutations have been identified in 13 genes encoding different cardiac ion channels or membrane adaptors.[4,5] The genetic and allelic heterogeneity results in subtly different clinical phenotypes.[6]. Several clinical syndromes have been described: RomanoWard syndrome (RWS), an autosomal dominant form of cLQTS, which presents clinically with a pure cardiac phenotype; Jervell and Lange-Nielsen syndrome (JLNS), an autosomal recessive form of LQTS which is associated with congenital deafness;[2] Andersen-Tawil syndrome (ATS), which is an autosomal dominant multisystem disorder where cLQTS is variably present; and Timothy syndrome (TS), which is characterised by severe cLQTS as well as cardiac and somatic malformations

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