Yield and clinical utility of the ‘molecular autopsy’ in cases of the Sudden Arrhythmic Death Syndrome (SADS) and their families

Post-mortem genetic testing (‘molecular autopsy’) of sudden arrhythmic death syndrome (SADS) cases can establish a clear molecular diagnosis in a substantial minority. This complements family evaluation. Classification of pathogenicity of genetic variants must, however, be stringent in order to avoid the over calling of variants of unknown significance as causative. Children and young adults presenting with seizures and syncope, especially when associated with stress or exercise, require thorough cardiac evaluation in order to not miss catecholaminergic polymorphic ventricular tachycardia. Molecular autopsy should not however be restricted to the young as cases over 35 years old also carry diagnostic variants

The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy.

Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity