title: Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.
abstract: BACKGROUND
  Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion.
  
  
  RESULTS
  We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals).
  
  
  CONCLUSIONS
  KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.
authors.affiliation: Department of Human Genetics, Howard Hughes Medical Institute, Division of Cardiology, Salt Lake City, Utah, USA. igor.splawski@genetics.utah.edu
authors.forename: I
authors.initials: I
authors.lastname: Splawski
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.forename: K W
authors.initials: KW
authors.lastname: Timothy
authors.forename: M H
authors.initials: MH
authors.lastname: Lehmann
authors.forename: S
authors.initials: S
authors.lastname: Priori
authors.forename: J L
authors.initials: JL
authors.lastname: Robinson
authors.forename: A J
authors.initials: AJ
authors.lastname: Moss
authors.forename: P J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: J A
authors.initials: JA
authors.lastname: Towbin
authors.forename: G M
authors.initials: GM
authors.lastname: Vincent
authors.forename: M T
authors.initials: MT
authors.lastname: Keating
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype