MTMR4 variants have opposite gene-specific impact on life-threatening arrhythmic risk in type 1 and 2 long QT syndrome

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

doi:10.1093/eurheartj/ehag294

MTMR4 variants have opposite gene-specific impact on life-threatening arrhythmic risk in type 1 and 2 long QT syndrome

Eur Heart J. 2026 May 13:ehag294. doi: 10.1093/eurheartj/ehag294. Online ahead of print.

Authors

Peter J Schwartz¹, Annika Winbo^{2

3}, Luca Sala^{1

4}, Lia Crotti^{1

5}, Giulia Musu¹, Federica Dagradi¹, Fulvio L F Giovenzana¹, Davide F Dragani⁵, Kotryna Simonyté Sjödin², Jenny Lundström², Chiara Alberio¹, Matteo Pedrazzini¹, Bruce D Nearing⁶, Annika Rydberg², Hung-Fat Tse⁷, Fabio Badilini^{8

9}, Richard L Verrier¹⁰, Carla Spazzolini¹, Massimiliano Gnecchi^{11

12}

Affiliations

¹ Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Via Pier Lombardo, 22, Milan 20135, Italy.
² Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
³ Department of Public Health and Clinical Medicine, Faculty of Medicine, Umeå University, Umeå, Sweden.
⁴ Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
⁵ Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
⁶ Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁷ Division of Cardiology, Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong SAR, China.
⁸ Division of Cardiology, University of California, San Francisco, CA, USA.
⁹ Department of Research and Development, AMPS-LLC, NewYork, NY, USA.
¹⁰ Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹¹ Department of Cardiothoracic and Vascular Sciences-Translational Cardiology Unit, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, Pavia 27100, Italy.
¹² Department of Molecular Medicine, Cardiology Unit, University of Pavia, Pavia, Italy.

PMID: 42128250
DOI: 10.1093/eurheartj/ehag294

Abstract

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.

Keywords: MTMR4; Arrhythmias; Induced pluripotent stem cell-derived cardiomyocytes; Long QT syndrome; NEDD4L; Sudden cardiac death.

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Abstract

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