KCNH2 p.Gly262AlafsTer98: A New Threatening Variant Associated with Long QT Syndrome in a Spanish Cohort

Abstract

Long QT syndrome (LQTS) is an inherited (autosomal dominant) channelopathy associated with susceptibility to ventricular arrhythmias due to malfunction of ion channels in cardiomyocytes, that could lead to sudden death (SD). Most pathogenic variants are in the main 3 genes: KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3). Efforts to improve the understanding of the genotype-phenotype relationship are essential to improve the medical clinical practice. In this study, we identified all index patients referred for NGS genetic sequencing due to LQTS, in a Spanish cohort, who were carriers of a new pathogenic variant (KCNH2 p.Gly262AlafsTer98). Genetic and clinical family screening was performed in order to describe its phenotypic characteristics. We identified 22 relatives of Romani ethnicity, who were carriers of the variant. Penetrance reached a 100% and adherence to medical treatment was low. There was a high rate of clinical events, particularly arrhythmic events and SD (1 in every 4 patients presented syncope, 1 presented an aborted SD, 2 obligated carriers suffered SD before the age of 40 and 4 out of 6 carriers of an implantable cardioverter-defibrillator (ICD) had appropriate ICD therapies. Correct adherence to medical treatment in all carriers should be specially encouraged in this population. ICD implantation decision in non-compliant patients, and refusing left cardiac sympathetic denervation, should be carefully outweighed.

Keywords: KCNH2 gene; genetic testing; inheritable arrhythmogenic disorder; long QT syndrome.

Figure 1

KCNH2 p.Gly262AlafsTer98 carriers: Family pedigrees. ICD, implantable cardioverter-defibrillator; SD, sudden death. Age of deceased in patients due to SD, in brackets. Symbols denote sex and disease status: “+”, carriers; “−”, noncarriers; without sign, genetic status unknown; box, male; circle, female; black darkened, long QT syndrome phenotype (prolonged QTc in electrocardiogram); grey darkened, unexplained SD; symbol clear, negative phenotype (normal QTc); “?”, unknown phenotype; slashed, deceased; arrow, proband.

Figure 2

Two ECGs. (A) 17-year-old woman with long QT syndrome, a carrier of the KCNH2 variant. The ECG in sinus rhythm shows jagged T waves in typical precordial leads of LQTS type 2 (arrows) with a QTc of 530 ms. (B) ECG of his mother, also a carrier of the variant, and in turn, a carrier of ICD in secondary prevention. Sinus rhythm with jagged T waves and prolonged QTc is also seen (arrow). (C) Sudden aborted death of the mother. Subcutaneous ICD registry where appropriate therapy can be observed. Spontaneous torsade de pointes that is detected and effectively defibrillated by the device.