A novel KCNH2 frameshift mutation (c.46delG) associated with high risk of sudden death in a family with congenital long QT syndrome type 2

Abstract

Background The congenital long QT syndrome type 2 is caused by mutations in KCNH2 gene that encodes the alpha subunit of potassium channel Kv11.1. The carriers of the pathogenic variant of KCNH2 gene manifest a phenotype characterized by prolongation of QT interval and increased risk of sudden cardiac death due to life-threatening ventricular tachyarrhythmias. Results A family composed of 17 members with a family history of sudden death and recurrent syncopes was studied. The DNA of proband with clinical manifestations of long QT syndrome was analyzed using a massive DNA sequencer that included the following genes: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, ANK2, KCNJ2, CACNA1, CAV3, SCN1B, SCN4B, AKAP9, SNTA1, CALM1, KCNJ5, RYR2 and TRDN. DNA sequencing of proband identified a novel pathogenic variant of KCNH2 gene produced by a heterozygous frameshift mutation c.46delG, pAsp16Thrfs*44 resulting in the synthesis of a truncated alpha subunit of the Kv11.1 ion channel. Eight family members manifested the phenotype of long QT syndrome. The study of family segregation using Sanger sequencing revealed the identical variant in several members of the family with a positive phenotype. Conclusions The clinical and genetic findings of this family demonstrate that the novel frameshift mutation causing haploinsufficiency can result in a congenital long QT syndrome with a severe phenotypic manifestation and an elevated risk of sudden cardiac death.

A Novel Frameshift Mutation, KCNH2 [p.Asp896ArgfsX79], Leading to Malignant Ventricular Arrhythmia, Identified After Treatment of Gastrointestinal Bleeding

“…have reported a novel KCNH2 frameshift mutation (c.46delG) in a family with congenital LQTS2. 1 There was a high incidence of sudden cardiac death in this family, and repeated syncopal spells in the proband; thus, it was phenotypically very different from the proband reported in our case.…”

“…There is a marked reduction in the incidence of arrhythmic sudden cardiac death after LCSD; however, in high-risk patients with LQTS, recurrent lethal electric events have been reported in up to 50%. 1 LCSD is not an alternative to ICD, but rather, is complementary to it.…”