The Role of Molecular Autopsy in Concealed Cardiomyopathies

Some young people die suddenly even though they seemed healthy and their heart looks normal at autopsy. In many of these tragic cases, the most likely cause is a dangerous heart rhythm problem. Sometimes this rhythm problem is the first sign of an underlying heart muscle disease (medical term “cardiomyopathy”) that cannot yet be seen with standard tests. This is called concealed cardiomyopathy.

A molecular autopsy means doing genetic testing on blood or tissue that was collected after death. By analysing genes known to be involved in inherited heart muscle diseases and rhythm disorders, doctors can sometimes find disease-causing genetic changes (gene variants) even when the heart appears normal or shows only very subtle changes. These findings support the idea that an early, “hidden” phase of cardiomyopathy can cause fatal arrhythmias before any clear structural damage is visible.

The paper also shows that inflammation of the heart muscle (medical term “myocarditis”), which is often seen at autopsy in young people, may overlap with or caused by an underlying genetic cardiomyopathy. In these cases, myocarditis can act as a trigger that brings out the disease and causes the fatal arrhythmia. In some individuals who are genetically predisposed, myocarditis may be the first visible sign of an underlying cardiomyopathy.

Finding a pathogenic or likely pathogenic genetic variant through molecular autopsy not only helps explain why a sudden death occurred; it also has important consequences for the family. First-degree relatives can be offered clinical evaluation and targeted genetic testing to see whether they carry the same variant and may be at risk. Early diagnosis allows closer follow-up and preventive strategies in family members carrying the family´s genetic variant to reduce the chance of life-threatening arrhythmias. Because these situations are complex and emotionally difficult, they are best managed by a multidisciplinary team including pathologists, cardiologists, pediatricians, geneticists, genetic counsellors and psychologists.

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Campuzano O, Tirón C, Martínez-Barrios E, Greco A, Cruzalegui J, Chipa F, Cesar S, Merchan EF, Coll M, Fernández-Falgueras A,Brugada R, Ortega M, Molina N, Barberia E, Toro R, Oliva A, Grassi S, Sarquella-Brugada  G.

The Role of Molecular Autopsy in Concealed Cardiomyopathies. Genes (Basel). 2025 Oct 28;16(11):1273. doi: 10.3390/genes16111273. PMID: 41300724.

Prepared by A Greco and Ruth Biller.