title: Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing.
abstract: 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.
  
  
  METHODS
  Between 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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden. evalena.stattin@medbio.umu.se
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.forename: Ida Maria
authors.initials: IM
authors.lastname: Boström
authors.forename: Annika
authors.initials: A
authors.lastname: Winbo
authors.forename: Kristina
authors.initials: K
authors.lastname: Cederquist
authors.forename: Jenni
authors.initials: J
authors.lastname: Jonasson
authors.forename: Björn-Anders
authors.initials: BA
authors.lastname: Jonsson
authors.forename: Ulla-Britt
authors.initials: UB
authors.lastname: Diamant
authors.forename: Steen M
authors.initials: SM
authors.lastname: Jensen
authors.forename: Annika
authors.initials: A
authors.lastname: Rydberg
authors.forename: Anna
authors.initials: A
authors.lastname: Norberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004562:Electrocardiography; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation