title: KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1.
abstract: Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymousKCNQ1p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, inKCNQ1-encoded Kv7.1.
  
  
  
  419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overallKCNQ1transcript levels to assess the effect on splicing.
  
  
  
  For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the totalKCNQ1transcript levels.
  
  
  
  Our results provide the first evidence that synonymous variants outside the canonical splice sites inKCNQ1can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.
authors.affiliation: Mayo Medical School, Mayo Clinic, Rochester, Minnesota, USA.|Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Kapplinger
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Anders
authors.initials: A
authors.lastname: Erickson
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sirisha
authors.initials: S
authors.lastname: Asuri
authors.affiliation: Division of Heart Rhythm Services, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: McIntosh
authors.affiliation: Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Kerr
authors.affiliation: Gitxsan Health Society, Hazelton, British Columbia, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Department of Medicine, University of Western Ontario, London, Ontario, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tang
authors.affiliation: Division of Cardiology, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Shubhayan
authors.initials: S
authors.lastname: Sanatani
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Arbour
authors.affiliation: Mayo Medical School, Mayo Clinic, Rochester, Minnesota, USA.|Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA.|Division of Heart Rhythm Services, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.|Division of Pediatric Cardiology, Department of Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics*; D029597:Romano-Ward Syndrome / Q000235:genetics*
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: <i>KCNQ1</i>; First Nations; exon skipping; long QT syndrome; modifier