br Conflict of interest br Acknowledgments br Background of

Conflict of interest
Acknowledgments
Background of basic genetics The human genome contains approximately 3 billion nucleotide protein kinase g pairs contained in 23 chromosome pairs. Each chromosome contains hundreds to thousands of genes and the estimated 30,000 genes in the human genome express approximately 100,000 proteins [1]. The Human Genome Project (HGP) was proposed in the 1980s and was completed in 2003. The 1000 Genomes Project was conducted between 2008 and 2015, generating the largest public catalogue of human variations and genotype data. The completion of these projects provides a source book for biology, medicine, and genetic research. Sanger sequencing was used for the genetic screening of BrS and was considered the gold standard for DNA sequencing in the subsequent two and a half decades [2]. In the past few years, new technologies (large-insert clone arrays, oligonucleotide arrays, target-gene sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS)) have been developed, thus allowing the detection of medium- to large-sized genomic regions at a single nucleotide resolution. These technological genomic advancements are able to provide high-throughput screening and can detect genetic variations in patients with high accuracy and reduced cost. Although scientists and policy advisers deal intensively with the interpretation and handling of the onslaught and ambiguity of genome-wide data, we are rapidly moving toward a new era of genetic research for BrS, which is full of opportunities as well as a mountain of challenges.
Terminology
Clear clinical diagnosis of Brugada syndrome before genetic testing Many clinical conditions may lead to ST-segment elevation in the right precordial leads, which mimic the BrS ECG patterns. For example, exposure to some drugs and ionic imbalance may produce a Brugada-like ST-segment elevation. Previous reports have described this as an acquired Brugada syndrome or Brugada phenocopy. It presents with an ECG pattern identical to type I (Coved), type 2, or type 3 (Saddleback) Brugada patterns but differs etiologically from true BrS. Prior to diagnosis of the true or congenital Brugada syndrome, all of the following conditions should be ruled out (Table 1). Acquired BrS usually has an identifiable underlying condition that elicits a BrS ECG pattern. Once the underlying condition is resolved, the ECG normalizes completely. Provocative testing with flecainide, ajmaline, pilsicainide, procainamide, or other sodium channel blockers is an important method to differentiate congenital BrS from acquired BrS. The result of these tests should be negative in patients with acquired BrS. The flowchart for such testing is shown in Fig. 2.
Genetic background of Brugada syndrome In 1996, the term “Brugada syndrome” was used to describe what was known as “right bundle branch block, persistent ST segment elevation, and sudden death syndrome”[7]. In 1998, the first BrS-associated gene, SCN5A, which encodes the alpha-subunit of the voltage-gated Nav1.5 cardiac sodium channel, was reported to be associated with the disease [8]. In the past 2 decades, several BrS-associated genes and modifier genes were reported and most of these primarily encode sodium, potassium, and calcium channels or the proteins associated with these channels (Table 2 and Fig. 3). Despite these genetic studies, only 30–35% of clinically diagnosed cases can be genetically diagnosed, indicating that 65–70% of BrS patients remain genetically unresolved.
The role of genetic testing in the clinical practice for Brugada syndrome BrS is partly a cardiac disorder, with an autosomal dominant inheritable model showing incomplete penetrance. The current expert consensus statement recommends mutation-specific genetic testing for family members and appropriate relatives following identification of the BrS-causative mutation in an index patient (Class I recommendation) [62]. The primary role of genetic testing in BrS is to confirm the disorder in the index patient, and cascade testing in relatives to distinguish those who need clinical follow-up (for development of conduction disease or syncopal episodes) and preventive measures (e.g., avoiding specific drugs, prompt management of fever) from those who are both clinically and genetically unaffected [56,63].