Abstract
BackgroundThe 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.ResultsA 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.ConclusionsThe 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.
Highlights
The congenital long QT syndrome type 2 is caused by mutations in Potassium voltagegated channel subfamily H member 2 (KCNH2) gene that encodes the alpha subunit of potassium channel Kv11.1
The long QT syndrome (LQTS) type 2 represents 30–45% of all cases of LQTS [8]. It is caused by mutations in the KCNH2 gene that encodes the alpha subunit of voltage dependent
We report a novel pathogenic variant of KCNH2 in a family whose members manifest LQTS type 2 with high penetrance and severe phenotype characterized by long QT interval, recurrent syncopes and multiple family antecedents of sudden death
Summary
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. The congenital long QT syndrome (LQTS) is characterized by prolongation of QT interval on the electrocardiogram (ECG) and increased risk of sudden cardiac death due to life-threatening ventricular tachyarrhythmias like torsades de pointes and ventricular fibrillation [1,2,3]. The LQTS type 2 represents 30–45% of all cases of LQTS [8] It is caused by mutations in the KCNH2 gene that encodes the alpha subunit of voltage dependent
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