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The molecular autopsy and inherited cardiac disease

  • Method

The molecular autopsy is postmortem genetic testing that looks for an inherited disease when the autopsy does not explain a sudden death.

Updated

What it is

The molecular autopsy (guidelines prefer the term postmortem genetic testing) analyses the dead person's DNA for variants in ion-channel and cardiomyopathy genes. It is indicated above all in sudden deaths of young people with a structurally normal heart and negative toxicology, where a channelopathy is suspected (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia), and when the autopsy shows an inherited cardiomyopathy. Its greatest value is for the living: it allows cascade testing of relatives. It requires the right sample to have been kept at autopsy and expert interpretation, because many variants are of uncertain significance.

Accuracy and limits

  • Formalin-fixed, paraffin-embedded samples are not ideal for DNA.
  • A variant of uncertain significance must not be used for medico-legal conclusions or to treat relatives.
  • European guidelines recommend referring first-degree relatives if the cause remains unexplained up to age 40, or if there is an inherited cardiomyopathy at any age.
  • Protocols and sample quality vary between centres, so standardisation is called for.
  • A negative result does not rule out an inherited disease.

What it is based on

  • Channelopathies leave no trace in the heart: only DNA can reveal them.
  • Inherited cardiomyopathies (hypertrophic, arrhythmogenic, dilated) are visible at autopsy, but the gene confirms the family's risk.
  • Sequencing gene panels chosen according to the findings is the most widely used method.

How it is applied

  1. At autopsy, keep EDTA blood and a piece of heart or spleen frozen.
  2. Complete the heart examination with histology and toxicology first.
  3. Select the cases: young people with unexplained sudden death or with an inherited cardiomyopathy.
  4. Analyse a gene panel chosen by the findings, in an experienced laboratory.
  5. Classify each variant as pathogenic, likely pathogenic or of uncertain significance.
  6. Refer first-degree relatives to cardiology and genetic counselling.

Next step: what to do and document

  • In every sudden death of a young person, ask for EDTA blood and frozen tissue to be kept at autopsy.
  • Ask the family about sudden deaths, fainting, seizures or unexplained drownings in other relatives.
  • Explain to the family, in plain language, why first-degree relatives should be screened, and refer them to cardiology.
  • Treat genetic information as sensitive data: share it with the family with their consent and in confidence.
  • If testing cannot be done straight away, record in the report which samples were kept and where they are.

Common mistakes

  • Not keeping EDTA blood or frozen tissue and relying on paraffin only.
  • Interpreting a variant of uncertain significance as the cause of death.
  • Requesting genetics without first ruling out poisoning and other causes.
  • Not informing the family or referring them for screening.

Test yourself

Think of the answer, then tap the question to see it.

When is a molecular autopsy indicated?

In unexplained sudden deaths of young people with a normal heart and negative toxicology, and when the autopsy shows an inherited cardiomyopathy.

Which samples are kept at autopsy for genetic testing?

EDTA blood and a frozen piece of heart or spleen; paraffin-embedded tissue is not ideal.

Why can a channelopathy only be diagnosed by genetics after death?

Because it is an electrical disorder that leaves no visible lesion in the heart or on histology.

Who benefits most from a molecular autopsy?

The living relatives, who can undergo cascade testing and receive prevention.

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Educational content on forensic and legal medicine; not legal advice and no substitute for the technical guides of Colombia's National Institute of Legal Medicine and Forensic Sciences. Laws change: each page links the official text and says when it was last checked. For a real case, follow the guide in force and ask the competent authority.

Sources: Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology (Virchows Archiv (PMC), 2017); New Insights on Molecular Autopsy in Sudden Death: A Systematic Review (Diagnostics (PMC), 2024); Autopsy and sudden death (European Heart Journal Supplements (PMC), 2023).

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