Feasibility and preliminary results of the GenetiCA study: evaluation of genetic-molecular causes of out-of-hospital cardiac arrest - from patients to families

Abstract

Inherited arrhythmogenic and structural cardiomyopathies represent the leading cause of out-of-hospital cardiac arrests (OHCAs) in the young. Previous studies focusing exclusively on OHCA survivors have identified inherited cardiovascular diseases (CVD) in 11–40% of cases. to assess the prevalence of genetic variants in genes associated with CVD among young patients experiencing OHCA due to medical causes in Lombardy Region, Italy. This is a prospective study including all OHCA occurring in individuals ≤50 years of age due to medical causes in Pavia province from 5/2021 to 12/2025. Following this initial phase, enrollment was extended to the entire Lombardy Region in 1/2026. Blood samples were collected, and Next Generation Sequencing was performed using a multigene panel targeting genes associated with CVD. Genetic variants were classified according to the American College of Medical Genetics and Genomics guidelines. Family-based genetic and clinical screening was offered when a pathogenic (P) or likely pathogenic (LP) variant was identified. An additional evaluation of "hot" variants of uncertain significance (VUS) was conducted based on the geneticist’s recommendation. In the pilot study, 2457 OHCA cases were recorded; 118 met the inclusion criteria, and 68 underwent genetic testing (4 tests are still ongoing). At least 1 genetic variant was detected in 29 patients (43%), and 8 (13%) carried at least 1 LP/P variant. Family genetic and clinical screening has been completed in 5 cases: in 2 patients, autopsy demonstrated acute coronary syndrome as the cause of death, unrelated to the identified variants (TTN and LAMA2, respectively); in 1 case, two LP/P variants in trans in the GAA gene were identified, although no clinical signs were observed in the victim; family screening revealed heterozygous variants consistent with autosomal recessive late-onset Pompe Disease; in another case, the post-resuscitation imaging showed cerebellar hemorrhage, which was not consistent with the identified LP variant in MYH7; in the last patient, a P variant in GAA and two VUS in DSP were detected, compatible with post-OHCA diagnosis of non-dilated left ventricular cardiomyopathy. Family segregation analysis is currently ongoing and may lead to variant reclassification. The extended analysis started in 2026 across the entire region has so far enrolled 22 new subjects (44% of the 50 new patients eligible for enrolment), whose genetic analyses are currently underway. GenetiCA study is currently the largest real-world assessment of inherited CVD among young OHCA patients within an entire geographical area of 10 million inhabitants. Preliminary results highlight the importance of genetic testing correlating with clinical autopsy to establish the causality of death. The study aims to clarify the genetic bases of OHCA with potential impact on epidemiology and preventive medicine.