Sudden cardiac death in persons aged 50 years or younger: diagnostic yield of a regional molecular autopsy program using massive sequencing.

Ripoll-Vera, Tomás; Pérez Luengo, Consuelo; Borondo Alcázar, Juan Carlos; García Ruiz, Ana Belén; Sánchez Del Valle, Nieves; Barceló Martín, Bernardino; Poncela García, Juan Luis; Gutiérrez Buitrago, Gloria; Dasi Martínez, Concepción; Canós Villena, Juan Carlos; Moyano Corvillo, Susana; Esgueva Pallarés, Raquel; Sancho Sancho, Juan Ramón; Guitart Pinedo, Gemma; Hernández Marín, Elena; García García, Estela; Vingut López, Albert; Álvarez Rubio, Jorge; Govea Callizo, Nancy; Gómez Pérez, Yolanda; Melià Mesquida, Catalina; Heine, Damián; Rosell Andreo, Jordi; Socías Crespí, Lorenzo

INTRODUCTION AND OBJECTIVES Sudden cardiac death (SCD) in young people often has a genetic cause. Consequently, the results of "molecular autopsy" may have important implications for their relatives. Our objective was to evaluate the diagnostic yield of a molecular autopsy program using next-generation sequencing. METHODS We performed a prospective study of a cohort of consecutive patients who died from nonviolent SCD, aged ≤ 50 years, and who underwent molecular autopsy using large panels of next-generation sequencing, with subsequent clinical and genetic family screening. We analyzed demographic, clinical, toxicological, and genetic data. RESULTS We studied 123 consecutive cases of SCD in persons aged ≤ 50 years. The incidence of SCD was 5.8 cases/100 000 individuals/y, mean age was 36.15±12.7 years, and 95 were men (77%). The cause was cardiac in 53%, unexplained SCD in 24%, toxic in 10.6%, and infant SCD in 4%. Among cardiac causes, ischemic heart disease accounted for 38% of deaths, arrhythmogenic cardiomyopathy for 7%, hypertrophic cardiomyopathy for 5%, and idiopathic left ventricular hypertrophy for 11%. Genetic analysis was performed in 62 cases (50.4%). Genetic variants were found in 42 cases (67.7%), with a mean of 3.4±4 genetic variants/patient, and the variant found was considered to be pathogenic or probably pathogenic in 30.6%. In unexplained SCD, 70% showed some genetic variant. Family screening diagnosed 21 carriers or affected individuals, 5 of whom were at risk, indicating an implantable cardiac defibrillator. CONCLUSIONS Protocol-based and exhaustive study of SCD from cardiac causes in persons aged ≤ 50 years is feasible and necessary. In a high percentage of cases, the cause is genetic, indicating the existence of relatives at risk who could benefit from early diagnosis and treatment to avoid complications.