Genetic defects in young out-of-hospital cardiac arrest (OHCA) patients in our city: the GenetiCA study

Abstract Introduction Out-of-hospital cardiac arrests (OHCA) in young patients (≤50 years) are reported to be linked to genetically determined cardiovascular diseases in 11–40% of cases. Most genetic studies focus on survivors or victims with available autopsy findings, while homogeneous, population-wide genetic analyses remain lacking Purpose To assess the prevalence of likely pathogenic/pathogenic (LP/P) variants in genes linked to heritable cardiovascular diseases in young (≤50 years) OHCA victims due to medical causes, regardless of autopsy Methods This prospective, longitudinal study includes all consecutive OHCAs (≤50 years) due to medical causes in Pavia province, Italy (May 2021–Jan 2025) in whom advanced resuscitation has been started by the Emergency Medical System (EMS). Blood samples were collected during pre-hospital resuscitation by EMS, and NGS-based multigene panel testing was performed. Genetic variants were classified based on ACMG guidelines, integrating segregation data when feasible. Results Among 2011 OHCA cases, 94 met inclusion criteria, and 49 underwent genetic testing. LP/P variants linked to heritable cardiovascular diseases were identified in 6 cases (12%), including 1 survivor (Table). Variants of uncertain significance were excluded. Forensic autopsy was performed in 2 of 5 deceased victims, documenting an acute coronary thrombosis as the unconfutable cause of death in both cases. In 3 cases (1-3), we could deeply inform, offer, and perform family genetic and clinical screening; in 3 cases, this has not been possible (case 4), is ongoing (case 5), and unneeded (case 6). In case 1, the lack of parental data limits the evaluation of the segregation of the TTN variant; the cause of death was the acute coronary thrombosis. In case 2 (no autopsy), the identification of two LP/P trans variants in GAA gene has no phenotypic and pathologic assessment in the victim. The family screening identified heterozygous variants in clinically healthy relatives, consistent with an autosomal recessive Late-Onset-Pompe Disease. In case 3, the genetically-predicted autosomal recessive merosin deficiency remains unconfirmed (clinically and pathologically unproven). At present, none of the heterozygous relatives is affected. The cause of death however is attributable to the acute coronary event identified at autopsy. In case 5, the post-resuscitation imaging showed massive cerebellar hemorrhage; despite decompression, the patient died Conclusions In our study, post-resuscitation imaging and autopsy clarified the cause of death in 1 and 2 OHCA victims, respectively, carriers of LP/P defects in genes associated with heritable cardiovascular diseases. Without autopsy or imaging, identifying pathogenic variants alone does not establish causality. A proposed law of the Italian Parliament (n.1807) aims to mandate autopsy and molecular analysis in sudden death cases, potentially reshaping epidemiology and preventing further events in the familiesTable