# MTMR4-modifier heeft tegenovergestelde invloed op aritmierisico bij LQT1 en LQT2

*geplaatst 2026-06-22 · Algemeen · European heart journal · doi 10.1093/eurheartj/ehag294 · https://hartvaat.nl/2026/05/13/mtmr4-modifier-heeft-tegenovergestelde-invloed-op-aritmierisico-bij-lqt1-en-lqt2/*

Studie bij 1.192 patiënten met lang-QT-syndroom (LQT1 n=638, LQT2 n=432, en 122 Zweedse dragers van de p.Y111C-LQT1-mutatie), waarin de invloed van varianten in het modifiergen MTMR4 op klinisch ernstige uitkomsten (hartstilstand of syncope onder bètablokker) werd onderzocht. In de LQT1-cohort daalde het percentage cardiale events significant met toenemende aa-genotype-frequentie (AA 15,9% → Aa 11,6% → aa 6,3%); in LQT2 was het patroon omgekeerd (AA 16,5% → Aa 18,2% → aa 27,6%). In de gecombineerde LQT1-cohort was aa aanwezig bij 15% van milde/asymptomatische patiënten versus 1,7% van patiënten met ernstige symptomen (p=0,002); bij LQT2 juist 24,1% versus 11,9% (p=0,014). QTc verschilde niet, maar repolarisatiemarkers (Tpeak-Tend) ondersteunden het genspecifieke patroon. De MTMR4-minor allel-homozygotie heeft dus een gen-specifieke, omgekeerde invloed op aritmierisico — relevant voor risicostratificatie.

## English: 

Study in 1,192 long-QT syndrome (LQTS) patients (LQT1 n=638, LQT2 n=432, plus 122 Swedish carriers of the p.Y111C-LQT1 mutation), investigating the impact of MTMR4 modifier-gene variants on severe clinical outcomes (cardiac arrest or syncope on beta-blockers). In the LQT1 cohort, the percentage of cardiac events decreased significantly with increasing aa-genotype frequency (AA 15.9% → Aa 11.6% → aa 6.3%); in LQT2 the pattern was reversed (AA 16.5% → Aa 18.2% → aa 27.6%). In combined LQT1, aa was present in 15% of mild/asymptomatic vs 1.7% of severe cases (p=0.002); in LQT2, 24.1% vs 11.9% (p=0.014). QTc did not differ, but repolarization markers (Tpeak-Tend) supported the gene-specific directionality. The MTMR4 minor-allele homozygosity has a gene-specific, opposite impact on arrhythmic risk — relevant for risk stratification.

## Abstract (original, from the publication)

BACKGROUND AND AIMS: Modifier genes may cause different clinical phenotypes in patients with long QT syndrome (LQTS) carrying the same pathogenic variant. Variants in the MTMR4 gene have been previously associated, via patient-specific cardiomyocytes derived from induced pluripotent stem cells, with variable arrhythmic risk in a family with the p.Y111C-LQT1 mutation. This study aimed to evaluate the broader clinical impact of MTMR4 variants in patients with LQT1 and LQT2. METHODS: A total of 1192 LQTS patients were analysed: 638 with LQT1, 432 with LQT2, and 122 Swedish carriers of the p.Y111C-LQT1 variant. The association between MTMR4 variants and clinical severity was assessed by comparing patients with severe symptoms (cardiac arrest or syncope on beta-blockers) vs asymptomatic or mildly symptomatic individuals. ECG parameters, including Tpeak-Tend and T-wave heterogeneity, were also evaluated. RESULTS: In the LQT1 cohort, there was a significant decreasing pattern for cardiac events across MTMR4 genotypes (AA:15.9%, Aa:11.6%, aa:6.3%), while an opposite trend was apparent in the LQT2 cohort (AA:16.5%, Aa:18.2%, aa:27.6%). No pattern was apparent in the Swedish cohort. In the combined LQT1 cohort, the aa genotype was found in 15% of 702 mild/asymptomatic vs 1.7% of 58 with severe symptoms (P = .002). Vice versa, in LQT2, aa was more frequent in severe cases (24.1% vs 11.9%, P = .014). QTc was not associated with MTMR4, but the repolarization markers supported a gene-specific directionality of arrhythmic risk. CONCLUSIONS: The MTMR4 minor allele in homozygosis exerts a gene-specific and opposite impact on arrhythmic risk in LQTS. This finding should influence risk stratification in clinical practice.

Auteurs: Peter J Schwartz, Annika Winbo, Luca Sala, Lia Crotti, Giulia Musu, Federica Dagradi, Fulvio L F Giovenzana, Davide F Dragani, Kotryna Simonyté Sjödin, Jenny Lundström, Chiara Alberio, Matteo Pedrazzini, Bruce D Nearing, Annika Rydberg, Hung-Fat Tse, Fabio Badilini, Richard L Verrier, Carla Spazzolini, Massimiliano Gnecchi

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Bron: European heart journal, https://doi.org/10.1093/eurheartj/ehag294. Bijgewerkt 2026-07-03T13:32:00Z. Citeer vrij, met bronvermelding en een link naar hartvaat.nl (de url van het record). Samenvattingen zijn redactioneel werk van HartVaat; de oorspronkelijke publicaties blijven van hun uitgevers (doi). Geen medisch advies.