Background
The use of next-generation sequencing enables a rapid analysis of many genes associated
with sudden cardiac death in diseases like Brugada Syndrome. Genetic variation is identified
and associated with 30–35% of cases of Brugada Syndrome, with nearly 20–25%
attributable to variants in SCN5A, meaning many cases remain undiagnosed genetically.
To evaluate the role of genetic variants in arrhythmogenic diseases and the utility of nextgeneration
sequencing, we applied this technology to resequence 28 main genes associated
with arrhythmogenic disorders.
Materials and Methods
A cohort of 45 clinically diagnosed Brugada Syndrome patients classified as SCN5Anegative
was analyzed using next generation sequencing. Twenty-eight genes were resequenced:
AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP,
GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNQ1,
NOS1AP, PKP2, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, and TMEM43. A total of
85 clinically evaluated relatives were also genetically analyzed to ascertain familial
segregation.
Results and Discussion
Twenty-two patients carried 30 rare genetic variants in 12 genes, only 4 of which were previously
associated with Brugada Syndrome. Neither insertion/deletion nor copy number variation
were detected. We identified genetic variants in novel candidate genes potentially
associated to Brugada Syndrome. These include: 4 genetic variations in AKAP9 including a de novo genetic variation in 3 positive cases; 5 genetic variations in ANK2 detected in 4 cases; variations in KCNJ2 together with CASQ2 in 1 case; genetic variations in RYR2,
including a de novo genetic variation and desmosomal proteins encoding genes including
DSG2, DSP and JUP, detected in 3 of the cases. Larger gene panels or whole exome
sequencing should be considered to identify novel genes associated to Brugada Syndrome.
However, application of approaches such as whole exome sequencing would difficult the
interpretation for clinical purposes due to the large amount of data generated. The identification
of these genetic variants opens new perspectives on the implications of genetic background
in the arrhythmogenic substrate for research purposes.
Conclusions
As a paradigm for other arrhythmogenic diseases and for unexplained sudden death, our
data show that clinical genetic diagnosis is justified in a family perspective for confirmation
of genetic causality. In the era of personalized medicine using high-throughput tools, clinical
decision-making is increasingly complex
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