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

Abstract

BackgroundLong 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.MethodsBetween March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umeå 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).ResultsIn 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.ConclusionIn 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.

Genetic analysis, in silico prediction, and family segregation in long QT syndrome

“…[12][13][14]16 In addition, also similar to a recent report, 34 we found a ratio near to 2:1 between women and men. Thus our population appears to be a representative sampling of Caucasian LQTS patients.…”

“…Previous studies indicated that 70-75% of patients carry a mutation in one of these five genes, [11][12][13] but recent studies have reported a similar genetic finding in close to 50% of LQTS patients. 14,16 The percentage increased to 75% when patients had a SSZ4. 13 According to the modified risk scores, 17 we analyzed patients with SSZ3.5.…”

“…12,13,16 Our population age ranged from birth to 77 years old. However, if we analyzed patients within an age range of diagnosis from birth to r40 years old, the percentage of patients with an identified mutation increased to 62.3%.…”

“…4,5 To date, mutations in five genes -KCNQ1 (KvLQT1 or Kv7.1, LQTS type 1) 6 and its associated b subunit KCNE1 (mink, LQTS type 5); 7 KCNH2 (hERG or Kv11.1, LQTS type 2) 8 and its associated b subunit KCNE2 (mirp1, LQTS type 6); 9 and SCN5A (Na v 1.5, LQTS type 3) 10 produce approximately 75% of LQTS cases. [11][12][13][14][15][16] Although 90% of LQTS mutations are localized in these five genes, pathogenic mutations have been reported for 11 other genes: ANK2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1, KCNJ5, CALM1, CALM2, 17 and RYR2. 18 Recent guidelines recommend genetic investigation of arrhythmias for clinical purposes.…”

Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis

“…We generated expression plasmids engineered with human variants associated with the LQTS variants KCNQ1-c.1553G>A/p.R518Q (a benign variant) (Kapplinger et al, 2009), truncating allele KCNQ1-c.1552C>T/p.R518X (Stattin et al, 2012), KCNQ1-c.532G>A/p.A178T (Tanaka et al, 1997;Kapplinger et al, 2009;Refsgaard et al, 2012) and KCNQ1-c.1085A>G/p.K362R (also associated with JLNS) (Tester et al, 2005;Kapplinger et al, 2009). All KCNQ1 alleles were transfected into mIMCD3 cells and, 24 h later, cells were transfected with non-targeting control siRNA or Kcnq1 siRNA (not targeting human KCNQ1).…”