Functional analysis in three probands suffering from “true” idiopathic ventricular fibrillation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F25%3A00142654" target="_blank" >RIV/00216224:14110/25:00142654 - isvavai.cz</a>

Result on the web

<a href="https://e-coretvasa.cz/contents/cor/2025/91.pdf" target="_blank" >https://e-coretvasa.cz/contents/cor/2025/91.pdf</a>

DOI - Digital Object Identifier

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Result language

angličtina

Original language name

Functional analysis in three probands suffering from “true” idiopathic ventricular fibrillation

Original language description

Variants in cardiac ion channel genes, common causes of various inherited arrhythmias, can be detected in some patients suffering from “true” idiopathic ventricular fibrillation (VF). These variants are frequently classified as variants of uncertain significance, thus, their causality is uncertain. Functional analysis is then the only way to consider their possible pathogenic character. We currently perform functional analysis on three probands suffering from idiopathic VF, the first one carrying two KCNH2 (hERG) variants (A228V and S1021Qfs*98; IKr channel), the second one a single RYR2 variant (Y4734C; RYR2 channel), and the third one a single SCN5A variant (M135V; INa channel). KCNH2 and SCN5A variants are tested using the whole-cell patch clamp technique on human ion channels with and without the specific variant transiently expressed in a cell line. The analysis revealed that S1021Qfs*98-KCNH2 is a pathogenic, dominant-negative variant with substantially decreased expression, resulting in a decrease of the repolarizing current through channels co-expressing A228V and S1021Qfs*98 variants by ~65 %. The pilot data in M135V channels show a decreased depolarizing current and several disturbances of gating, including rightward shifts of both activation and inactivation voltage dependences and faster recovery from inactivation. In the Y4734C-RYR2 variant, patient-specific hiPSC-derived cardiomyocytes of the proband, his sister with the same variant and diagnosis of catecholaminergic polymorphic ventricular tachycardia, and his healthy nephew were prepared and are being tested using the multielectrode array technique and simultaneous recording of Ca2+ transient and contraction (IonOptix). A significantly higher short-term variability of the cycle length in both control and proarrhythmic conditions (hypokalemia, fever, β-stimulation) was observed in both carriers of Y4734C-RYR2, the proband and his sister, compared to healthy cardiomyocytes of the proband ́s nephew; the highest irregularity of the rhythm was identified in the proband. Analysis under application of sex-hormones is followed to explain the differences between Y4734C-RYR2 cardiomyocytes of the male proband and his sister. Functional analysis enables detailed characterization of ion channel dysfunction. In the case of idiopathic VF, it may provide essential data for understanding arrhythmogenesis and for clinical management of both probands and previously asymptomatic carriers of the same variant.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30201 - Cardiac and Cardiovascular systems

Project

<a href="/en/project/NU22-02-00348" target="_blank" >NU22-02-00348: Functional assessment of genetic variants in clinically “true” cases of idiopathic ventricular fibrillation: in vitro and in silico modelling to reveal the arrhythmogenic mechanism</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů