TECRL, a new life‐threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT
Bibliographic record
Abstract
Abstract Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole‐exome sequencing ( WES ) was carried out on patients from three different families that presented with life‐threatening arrhythmias and high risk of sudden cardiac death ( SCD ). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans ‐2,3‐enoyl‐CoA reductase‐like protein. Both patients had cardiac arrest, stress‐induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia ( CPVT ) had a homozygous splice site mutation (c.331+1G>A) in TECRL . Analysis of intracellular calcium ([Ca 2+ ] i ) dynamics in human induced pluripotent stem cell‐derived cardiomyocytes (hi PSC ‐ CM s) generated from this individual ( TECRL H om ‐hi PSC s), his heterozygous but clinically asymptomatic father ( TECRL H et ‐hi PSC s), and a healthy individual ( CTRL ‐hi PSC s) from the same Sudanese family, revealed smaller [Ca 2+ ] i transient amplitudes as well as elevated diastolic [Ca 2+ ] i in TECRL H om ‐hi PSC ‐ CM s compared with CTRL ‐hi PSC ‐ CM s. The [Ca 2+ ] i transient also rose markedly slower and contained lower sarcoplasmic reticulum ( SR ) calcium stores, evidenced by the decreased magnitude of caffeine‐induced [Ca 2+ ] i transients. In addition, the decay phase of the [Ca 2+ ] i transient was slower in TECRL H om ‐hi PSC ‐ CM s due to decreased SERCA and NCX activities. Furthermore, TECRL H om ‐hi PSC ‐ CM s showed prolonged action potentials ( AP s) compared with CTRL ‐hi PSC ‐ CM s. TECRL knockdown in control human embryonic stem cell‐derived CM s ( hESC ‐ CM s) also resulted in significantly longer AP s. Moreover, stimulation by noradrenaline ( NA ) significantly increased the propensity for triggered activity based on delayed afterdepolarizations ( DAD s) in TECRL H om ‐hi PSC ‐ CM s and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT . Patient‐specific hi PSC ‐ CM s recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".