Abstract
Sudden cardiac death (SCD) is a serious public health problem. In the United States, more than 300,000 people are affected by SCD every year. Significantly, sudden deaths represent 20% of the total mortality and 50% of cardiovascular mortality in Western countries. In addition, SCD constitutes one of the most important unsolved challenges in the practice of forensic pathology because of the failure to determine the exact cause of sudden death. In young individuals, SCD is frequently caused by cardiomyopathies and channelopathies, that have generally an autosomal dominant pattern of inheritance. The impact of genetics and genetic testing on the clinical management of these diseases is unquestioned. In particular, genetic tests are an important tool for identifying pre-symptomatic individuals carrying genetic variant that predisposes them to SCD. High-throughput sequencing technologies offer novel opportunities to deeper investigate the genetic background underlying these fatal diseases and to early identify individuals at risk for SCD. In this review, we provide an overview of the development of Next-Generation Sequencing (NGS) technologies and of guidelines useful to design an efficient sequencing protocol and to perform an accurate data analysis. We suggest a flow chart to follow for the set up of a genetic screening protocol for the prevention of cardiac pathologies, in particular SCD events, in young athletes.
Highlights
DNA sequencing technologies have a broad range of applications in different fields, including molecular cloning and identification of pathogenic genes as well as comparative and evolutionary studies
Genetic tests are an important tool for identifying pre-symptomatic individuals carrying genetic variant that predisposes them to Sudden cardiac death (SCD)
We provide an overview of the development of Next-Generation Sequencing (NGS) technologies and of guidelines useful to design an efficient sequencing protocol and to perform an accurate data analysis
Summary
DNA sequencing technologies have a broad range of applications in different fields, including molecular cloning and identification of pathogenic genes as well as comparative and evolutionary studies. NGS has been applied to comprehensively study several Mendelian monogenic disorders as well as complex diseases including cancer (Navin and Hicks, 2011) and cardiac diseases (Fokstuen et al, 2014) For these multifactorial diseases, a very important advantage of NGS is the possibility of testing many genes in a relatively short time and with low cost. The simultaneous study of a large number of genes makes it possible to underline all of the mutations present in one patient and to analyze the possible correlation between these variants and the pathology This approach is very expensive and requires long analysis times, which comprise critical points for a diagnostic genetic test. The NGS data analysis produces a complete report that includes the following files: FASTQ (base calls of all the reads produced and the quality score of each base); BAM (the alignment of the reads over the reference genome); Variant Call File (VCF; the chromosomal position, name, and reference genome of each variant)
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