Di Resta Chiara, Pietrelli Alessandro, Sala Simone, Della Bella Paolo, De Bellis Gianluca, Ferrari Maurizio, Bordoni Roberta, Benedetti Sara
Vita-Salute San Raffaele University, Milan, Italy.
Institute of Biomedical Technologies, National Research Council of Italy (ITB-CNR), Milan, Italy, Molecular Medicine, University of Milan, Milan, Italy.
Hum Mol Genet. 2015 Oct 15;24(20):5828-35. doi: 10.1093/hmg/ddv302. Epub 2015 Jul 28.
Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder that can lead to sudden death, with a prevalence of 1:5000 in Caucasian population and affecting mainly male patients in their third to fourth decade of life. BrS is inherited as an autosomal dominant trait; however, to date genetic bases have been only partially understood. Indeed most mutations are located in the SCN5A gene, encoding the alpha-subunit of the Na(+) cardiac channel, but >70% BrS patients still remain genetically undiagnosed. Although 21 other genes have been associated with BrS susceptibility, their pathogenic role is still unclear. A recent next-generation sequencing study investigated the contribution of 45 arrhythmia susceptibility genes in BrS pathogenesis, observing a significant enrichment only for SCN5A. In our study, we evaluated the distribution of putative functional variants in a wider panel of 158 genes previously associated with arrhythmic and cardiac defects in a cohort of 91 SCN5A-negative BrS patients. In addition, to identify genes significantly enriched in BrS, we performed a mutation burden test by using as control dataset European individuals selected from the 1000Genomes project. We confirmed BrS genetic heterogeneity and identified new potential BrS candidates such as DSG2 and MYH7, suggesting a possible genetic overlap between different cardiac disorders.
布加综合征（BrS）是一种遗传性心律失常疾病，可导致猝死，在白种人群中的患病率为1:5000，主要影响30至40岁的男性患者。布加综合征以常染色体显性特征遗传；然而，迄今为止，其遗传基础仅得到部分了解。实际上，大多数突变位于编码心脏钠离子通道α亚基的SCN5A基因中，但仍有超过70%的布加综合征患者在基因方面未得到诊断。尽管还有其他21个基因与布加综合征易感性相关，但其致病作用仍不清楚。最近一项二代测序研究调查了45个心律失常易感基因在布加综合征发病机制中的作用，仅观察到SCN5A有显著富集。在我们的研究中，我们评估了158个先前与心律失常和心脏缺陷相关基因的假定功能变异在91例SCN5A阴性布加综合征患者队列中的分布情况。此外，为了鉴定在布加综合征中显著富集的基因，我们使用从千人基因组计划中选取的欧洲个体作为对照数据集进行了突变负荷测试。我们证实了布加综合征的遗传异质性，并鉴定出了新的潜在布加综合征候选基因，如DSG2和MYH7，这表明不同心脏疾病之间可能存在遗传重叠。
