A pathogenic TNNI3 p.Arg192His variant caused restrictive cardiomyopathy and sudden cardiac arrest in a 19-year-old female, confirming the diagnosis and enabling family cascade screening.
Genetic testing in young patients with restrictive cardiomyopathy and sudden cardiac arrest is crucial for confirming the diagnosis and enabling family cascade screening.
Abstract Introduction Restrictive cardiomyopathy (RCM) is defined as restrictive left and/or RV pathophysiology in the presence of normal or reduced diastolic volumes, normal or reduced systolic volumes, and normal ventricular wall thickness. When inherited, RCM most commonly presents as an autosomal dominant disorder. Although all major sarcomeric genes may cause RCM, the most common disease gene is TNNI3, which encodes the thin filament troponin I. Presentation We present the case of a 19-year-old female, originally from Cape Verde and living in Portugal, with prior follow-up at a pediatric cardiology center due to RCM with severe left ventricular disfunction (LVF) of unknown aetiology. Her family history included sudden death in her maternal grandmother (59 years) and maternal uncle (32 years). Her prescribed medications included lisinopril, carvedilol, furosemide, spironolactone, and dapagliflozin. She presented to the emergency department with acute chest pain, nausea, vomiting and dyspnea. ECG documented new atrial flutter with controlled ventricular rate. A few hours later, she developed ventricular fibrillation cardiac arrest, promptly reverted with one shock. Post-resuscitation ECG showed widespread ST-segment changes that normalized within 30 minutes. Transthoracic echocardiography revealed severe LV systolic dysfunction (LVF∼30%), diffuse hypokinesis, right ventricular dysfunction and severe biatrial dilatation. Cardiac MRI confirmed biventricular systolic dysfunction, severe biatrial dilatation, mild septal thickening, no ventricular late gadolinium enhancement (LGE) but atrial LGE (consistent with atrial remodelling). Endomyocardial biopsy revealed cardiomyocytes with large, irregular, hyperchromatic nuclei, displaying a bizarre morphology and arranged in a disorganized (disarray) pattern, consistent with sarcomeric cardiomyopathy. Coronary CT angiography excluded atherosclerosis. Genetic testing identified a heterozygous missense variant in the TNNI3 gene: NM₀00363. 5: c. 575GA (p. Arg192His). This variant has been classified as pathogenic and described in literature in some patients with restrictive cardiomyopathy and has autosomal dominant inheritance. During hospitalization, it was implanted a subcutaneous implantable cardioverter-defibrillator. She is currently under follow-up without recurrent arrhythmias, chest pain or heart failure. Patient will receive appropriated genetic counselling and cascade family screening is planned. Conclusion RCM has marked variability in presentation, which can delay diagnosis, and is associated with the worst prognosis of all the cardiomyopathy phenotypes. In this young patient with restrictive cardiomyopathy and a TNNI3 p. Arg192His variant, genetic testing was essential to confirm the diagnosis and enable family cascade screening, particularly given a family history of sudden cardiac death.
Silva et al. (2026) studied this question. A pathogenic TNNI3 p.Arg192His variant caused restrictive cardiomyopathy and sudden cardiac arrest in a 19-year-old female, confirming the diagnosis and enabling family cascade screening.