The MTMR4 minor allele in homozygosis (aa) was associated with a lower frequency of severe symptoms in LQT1 (1.7% vs 15%, P=0.002) but a higher frequency in LQT2 (24.1% vs 11.9%, P=0.014).
Cohort (n=1,192)
Do MTMR4 variants impact the risk of life-threatening arrhythmias in patients with type 1 and 2 long QT syndrome?
The MTMR4 minor allele in homozygosis has a gene-specific, opposite impact on arrhythmic risk in LQT1 versus LQT2, which may inform clinical risk stratification.
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.
Schwartz et al. (Wed,) conducted a cohort in Long QT syndrome (type 1 and 2) (n=1,192). MTMR4 variants was evaluated on Severe symptoms (cardiac arrest or syncope on beta-blockers). The MTMR4 minor allele in homozygosis (aa) was associated with a lower frequency of severe symptoms in LQT1 (1.7% vs 15%, P=0.002) but a higher frequency in LQT2 (24.1% vs 11.9%, P=0.014).