Yield of Molecular Autopsy in Sudden Cardiac Death in Athletes. Data from a Large Registry in the United Kingdom

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Gherardo Finocchiaro, Davide Radaelli, David Johnson, Raghav T Bhatia, Joseph Westaby, Stefano D’Errico, Michael Papadakis, Sanjay Sharma, Mary N Sheppard, Elijah R Behr. Europace. 2024 Jan 30.
Background: Sudden cardiac death (SCD) may occur in apparently healthy individuals, including athletes. We report the diagnostic role of post-mortem genetic testing, molecular autopsy (MA), in elucidating the cause of SCD in athletes.
Methods: We reviewed a database of 6860 consecutive cases of SCD referred to our specialist cardiac pathology centre. All cases underwent detailed cardiac autopsy and 748 were deemed to be athletes. Of these, 42 (6%) were investigated with MA (28 using a targeted sequencing, 14 exome sequencing). Variants were classified manually as pathogenic (P), likely pathogenic (LP), variant of unknown significance (VUS) using international guidelines. Clinical information was obtained from referring coroners who completed a detailed health questionnaire.
Results: Out of the 42 decedents (average age 35 years old, 98% males) who were investigated with MA, the autopsy was in keeping with a structurally normal heart (sudden arrhythmic death syndrome, SADS) in n = 33 (78%) cases, followed by arrhythmogenic cardiomyopathy (ACM) in 8 (19%) individuals and idiopathic left ventricular fibrosis in 1 (2%). Death occurred during exercise and at rest in 26 (62%) and 16 (38%) individuals respectively. Variants that were adjudicated clinically actionable were present in 7 cases (17%). There was concordance between the genetic and phenotypic findings in 2 cases of ACM. None of the variants identified in SADS cases were previously linked to channelopathies. Clinically actionable variants in cardiomyopathy-associated genes were found in 5 cases of SADS.
Conclusions: The yield of MA in athletes who died suddenly is 17%. In SADS cases, clinically actionable variants were found in cardiomyopathy-associated genes and not in channelopathy-associated genes. ACM is a common cause of SCD in athletes and one in four decedents had a clinically actionable variant in FLNC and TMEM43 genes.
Keywords: Molecular autopsy; sudden cardiac death.