Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing

Eva-Lena Stattin 0 1 4 Ida Maria Bostrm 0 1 4 Annika Winbo 1 3 Kristina Cederquist 0 1 4 Jenni Jonasson 0 1 4 Bjrn-Anders Jonsson 0 1 4 Ulla-Britt Diamant 1 2 Steen M Jensen 1 2 Annika Rydberg 1 3 Anna Norberg 0 1 4 0 Department of Medical Biosciences, Medical and Clinical Genetics, Umea University , Umea , Sweden 1 Methods: Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umea University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1 , KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore , the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT) 2 Heart Centre and Department of Public Health and Clinical Medicine, Umea University , Umea , Sweden 3 Department of Clinical Sciences, Paediatrics, Umea University , Umea , Sweden 4 Department of Medical Biosciences, Medical and Clinical Genetics, Umea University , Umea , Sweden Background: Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort. Results: In total, a disease-causing mutation was identified in 103 of the 200 (52%) index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death. Conclusion: In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the mutations and 3 of 36 selected cases (8%) harboured a mutation in the RYR2 gene. The mutation panorama is characterised by founder mutations (25%), even so, this cohort increases the amount of known LQTS-associated mutations, as approximately one-third (28%) of the detected mutations were unique. - Background Long QT syndrome (LQTS) is an autosomal dominant inherited arrhythmogenic disease and a significant cause of sudden cardiac death (SCD), usually in young and otherwise healthy individuals. LQTS is characterised by delayed ventricular repolarisation, seen as prolongation of the QT-interval on the electrocardiogram (ECG), which predisposes to Torsade-de-Pointes (TdP) and subsequent sudden death by ventricular fibrillation [1,2]. TdP or ventricular tachyarrhythmia is often selfterminating and presents as syncope with loss of consciousness, the most frequent symptom of LQTS. The phenotype is highly variable in expressivity and incomplete in penetrance [3]. Although the majority of LQTS patients show a diagnostic prolongation of the QTinterval on resting ECG, a normal ECG with a normal QTc is not enough to rule out LQTS, since up to approximately 40% of the patients may present with a normal QT-interval. A LQTS mutation carrier without prolonged QTc has a 10% risk of major cardiac events by the age of 40 years when left without treatment [4]. Cardiac events are often prompted by physical activity or by intense emotion or stress, but can also occur at rest or during sleep [5,6]. Exercise-induced syncope can also be caused by another inherited ion-channel disease, named catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterised by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system [7]. Some patients suspected to have LQTS might actually have CPVT, since there is a clinical overlap between these disorders [8,9]. The prevalence of LQTS has been estimated to 1/ 2,000 in the population [10]. To date, 13 different genes have been associated with LQTS, all encoding subunits of cardiac ion-channels (K+, Na+ or Ca2+) or ion-channel regulatory proteins [11]. More than 90% of the mutations are found in five of the genes (KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2), and mutation analysis of these five LQTS-causing genes reveals a mutation in about 75% of patients with a clinical diagnosis of LQTS [8,12-15]. Typically, the diseas (...truncated)