Targeted molecular genetic testing in young sudden cardiac death victims from Western Denmark

• Published in: International journal of legal medicine 2020, Vol.134 (1), p.111-121
• Main Authors: Larsen, Maiken Kudahl, Christiansen, Sofie Lindgren, Hertz, Christin Løth, Frank-Hansen, Rune, Jensen, Henrik Kjærulf, Banner, Jytte, Morling, Niels
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Autopsies; Cardiomyopathies - genetics; Cardiomyopathy; Child; Child, Preschool; Death, Sudden, Cardiac; Defibrillators; Denmark; Deoxyribonucleic acid; DNA; DNA - isolation & purification; Fatalities; Female; Forensic Medicine; Genes; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Hypertrophy, Left Ventricular - genetics; Infant; Male; Medical Law; Medicine; Medicine & Public Health; Myocardium - pathology; Original Article; Phenotype; Sequence Analysis, DNA
• ISSN: 0937-9827; 1437-1596
• DOI: 10.1007/s00414-019-02179-x

Sudden unexpected death in the young continues to be an important unsolved challenge. A significant proportion of the deaths are suspected to be caused by inherited cardiac diseases and are referred to as sudden cardiac deaths (SCD). We performed targeted molecular testing of 70 deceased individuals under 40 years of age that after forensic autopsy were suspected to have died of SCD. The individuals were previously genetically investigated using smaller numbers of genes associated with specific cardiac diseases. In our previous studies, seven (10%) individuals had pathogenic or likely pathogenic variants according to the 2015 ACMG guidelines. In order to investigate the value of expanding the panel to 100 genes associated with cardiac diseases, we histopathologically re-examined the 70 suspected SCD cases and grouped them according to phenotypes into suspected cardiomyopathy (the cardiomyopathy group), left ventricular hypertrophy (the hypertrophy group) and structural normal hearts (the SUD group). DNA was captured with the Haloplex target enrichment system and sequenced using an Illumina MiSeq. We found that 11 (16%) individuals harboured pathogenic or likely pathogenic variants. In the cardiomyopathy, hypertrophy and SUD groups, 22%, 6% and 17% of the individuals, respectively, harboured pathogenic or likely pathogenic variants. Our findings show that testing of a broad panel of genes associated with cardiac diseases identify potential pathogenic variants of cardiac diseases in a significant proportion of SCD cases, and this may have important implications in family screening to prevent future deaths.