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.

Calmodulin variant E140G associated with long QT syndrome impairs CaMKIIδ autophosphorylation and L-type calcium channel inactivation

“…It is characterized by prolongation of the QT interval on an ECG ( 2 ), caused by gain-of-function or loss-of-function mutations in cardiac ion channels that lead to prolongation of cellular repolarization ( 3 ). More than 90% of genetically confirmed cases of LQTS can be linked to mutations in potassium (K + ) or sodium (Na + ) channels ( 4 , 5 , 6 ). However, mutations in the highly conserved calcium (Ca 2+ )-sensing protein, calmodulin (CaM), have recently been implicated in LQTS ( 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ).…”

Concealed Inherited Cardiomyopathies Detected in Cardio-Oncology Screening

“…All patients who agreed to participate signed the informed consent for genetic testing (local Institutional Ethical Committee approval, CEImPA 2022.254). DNA was obtained from peripheral blood, and NGS analysis was performed, as reported elsewhere [ 22 , 23 , 24 , 25 , 26 ]. The NGS cardiovascular panel provided in our institution was designed with the aim of optimizing economic resources, attempting to be both time effective and cost effective.…”

Opportunistic Genetic Screening for Familial Hypercholesterolemia in Heart Transplant Patients

“…DNA was obtained from blood leukocytes by the salting-out method in all patients, and NGS was performed with a 205 cardiovascular-disease-associated gene panel, as previously reported [2]. DNA was sequenced by ion torrent technology using semiconductor chips in an Ion Gene Studio S5 Plus sequencer (Termo Fisher Scientific) according to a previously described procedure [10][11][12][13]. Raw data were processed with the Torrent Suite v5 pipeline.…”