title: KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome.
abstract: BACKGROUND
  Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same disease-causing mutation is usually attributed to variable penetrance. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common single nucleotide polymorphisms, altering arrhythmia susceptibility. We demonstrate this concept in a family segregating a novel, low-penetrant KCNH2 mutation along with a common single nucleotide polymorphism in the same gene.
  
  
  RESULTS
  The proband is a 44-year-old white woman with palpitations associated with presyncope since age 20, who presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed (max QTc, 530 ms), and LQT2 was diagnosed after the identification of a missense KCNH2 mutation (A1116V) altering a conserved residue in the distal carboxyl-terminus of the encoded HERG protein. The proband also carried the common KCNH2 polymorphism K897T on the nonmutant allele. Relatives who carried A1116V without K897T were asymptomatic, but some exhibited transient mild QTc prolongation, suggesting latent disease. Heterologous expression studies performed in cultured mammalian cells and using bicistronic vectors linked to different fluorescent proteins demonstrated that coexpression of A1116V with K897T together resulted in significantly reduced current amplitude as compared with coexpression of either allele with WT-HERG. Thus, the presence of KCNH2-K897T is predicted to exaggerate the IKr reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles.
  
  
  CONCLUSIONS
  We have provided evidence that a common KCNH2 polymorphism may modify the clinical expression of a latent LQT2 mutation. A similar mechanism may contribute to the risk for sudden death in more prevalent cardiac diseases.
authors.affiliation: Department of Cardiology, University of Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy.
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lundquist
authors.forename: Roberto
authors.initials: R
authors.lastname: Insolia
authors.forename: Matteo
authors.initials: M
authors.lastname: Pedrazzini
authors.forename: Chiara
authors.initials: C
authors.lastname: Ferrandi
authors.forename: Gaetano M
authors.initials: GM
authors.lastname: De Ferrari
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vicentini
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D016757:Death, Sudden, Cardiac / Q000209:etiology; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human