Key result
Rare TMEM175 missense variants are linked to ~11 ms shorter QTc intervals and familial SQTS.
Why the study?
Short QT syndrome is a rare cardiac channelopathy carrying an increased risk of sudden cardiac death, yet only 20-30% of cases have been linked to genetic mutations, which are typically in surface membrane ion channels.
Observational (n=118,000)
Yes
This study identifies the lysosomal potassium/proton channel mutation TMEM175 p.Arg377His as the first non-sarcolemmal ion channel defect causing Short QT Syndrome and sudden cardiac death via disruption of the lysosomal-mitochondrial axis.
Answers are grounded in this paper and cite their sources.
TMEM175 variants may explain some unexplained Short QT Syndrome; extends genetic etiology beyond membrane channels but leaves clinical adoption open.
Short QT Syndrome (SQTS) is a rare cardiac channelopathy characterized by abnormally short QTc intervals and increased sudden cardiac death (SCD) risk. Only 20-30% of SQTS cases have been linked to genetic mutations, typi-cally in surface membrane ion channels. We identified a novel lysosomal TMEM175 gene mutation (p.Arg377His) in 7 patients in a family with SQTS and SCD. Genetic analyses, including whole exome sequencing in the family and rare-variant burden testing in ∼118,000 UK Biobank participants, sug-gested an association between TMEM175 rare variants and QT interval short-ening. Functional studies in CRISPR-engineered mice and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) revealed that TMEM175R377H causes shortened QT intervals and hastened repolariza-tion, respectively, as well an increased arrhythmia susceptibility. Isolated TMEM175R377H cardiomyocytes showed action potential duration (APD) abbre-viation, confirmed in whole TMEM175R377H mouse hearts and patient-specific iPSC-CM monolayers. In silico and electron microscopy studies showed that TMEM175R377H disrupts lysosomal-mitochondrial interactions, leading to mito-chondrial dysfunction, as evidenced by the reduced maximal respiration and spare respiratory capacity, with reduced ATP production, IKATP activation, and APD shortening. This mutation represents the first non-sarcolemmal ion chan-nel defect associated with SQTS and high SCD risk, potentially expanding the genetic landscape of the disease.
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Cruz et al. (2026) conducted an observational in Short QT Syndrome (SQTS) and Sudden Cardiac Death (SCD) (n=118,000). TMEM175 rare missense variants (including p.Arg377His) vs. Wild-type / non-carriers was evaluated on QTc interval duration (ms) (MD -11.10 ms, p=0.00103). Rare TMEM175 missense variants were associated with an 11.10 ms shortening of the QTc interval and caused Short QT Syndrome in a family carrying p.Arg377His.