背景:Brugada综合征(BrS)是一种与心源性猝死相关的遗传性原发性通道病综合征。总的来说,已在18个编码离子通道亚基的基因和7个调节蛋白的基因中鉴定出变异。最近,在一名BrS表型阳性患者中发现了DLG1的错义变异.DLG1编码突触相关蛋白97(SAP97),特征在于存在用于蛋白质-蛋白质相互作用的多个结构域(包括PDZ结构域)的蛋白质。在心肌细胞中,SAP97与Nav1.5相互作用,Nav1.5是SCN5A的PDZ结合基序和其他钾通道亚基。
目的:描述一个携带DLG1变异体的BrS综合征意大利家族的表型特征。
方法:进行临床和遗传学调查。使用Illumina平台用全外显子组测序(WES)进行遗传测试。根据标准协议,通过双向毛细管Sanger重测序,在该家族的所有成员中确认了WES发现的一个变体。通过使用致病性的计算机预测来研究变体的效果。
结果:该指标病例是一名74岁男性,患有自发性1型BrS心电图,经历晕厥并接受ICD植入。索引案例的WES,假设继承的主导模式,鉴定出一个杂合变异体,c.1556G>A(p。R519H),在DLG1基因的外显子15中。在血统调查中,12个家庭成员中有6个具有该变体。该基因变异的携带者均患有BrSECG1型药物诱导并表现出异质性心脏表型,其中两名患者在运动和发烧期间出现晕厥,分别。氨基酸残基#519位于PDZ结构域附近,并且计算机模拟分析表明该变体的因果作用。对所得蛋白质结构的建模预测该变体破坏了H-键和致病性的可能性。因此,构象变化可能会影响蛋白质的功能和对离子通道的调节作用。
结论:鉴定出的DLG1基因变异与BrS相关。该变体可以修饰多通道蛋白复合物的形成,影响离子通道到心肌细胞的特定区室。
Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated to sudden cardiac death. Overall, variants have been identified in eighteen genes encoding for ion channel subunits and seven genes for regulatory proteins. Recently, a missense variant in DLG1 has been found within a BrS phenotype-positive patient. DLG1 encodes for synapse associated protein 97 (SAP97), a protein characterized by the presence of multiple domains for protein-protein interactions including PDZ domains. In cardiomyocytes, SAP97 interacts with Nav1.5, a PDZ binding motif of SCN5A and others potassium channel subunits.
To characterize the phenotype of an Italian family with BrS syndrome carrying a DLG1 variant.
Clinical and genetic investigations were performed. Genetic testing was performed with whole-exome sequencing (WES) using the Illumina platform. According to the standard protocol, a variant found by WES was confirmed in all members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using in silico prediction of pathogenicity.
The index case was a 74-year-old man with spontaneous type 1 BrS ECG pattern that experienced syncope and underwent ICD implantation. WES of the index case, performed assuming a dominant mode of inheritance, identified a heterozygous variant, c.1556G>A (p.R519H), in the exon 15 of the DLG1 gene. In the pedigree investigation, 6 out of 12 family members had the variant. Carriers of the gene variant all had BrS ECG type 1 drug induced and showed heterogeneous cardiac phenotypes with two patients experiencing syncope during exercise and fever, respectively. The amino acid residue #519 lies near a PDZ domain and in silico analysis suggested a causal role for the variant. Modelling of the resulting protein structure predicted that the variant disrupts an H-bond and a likelihood of being pathogenic. As a consequence, it is likely that a conformational change affects protein functionality and the modulating role on ion channels.
A DLG1 gene variant identified was associated with BrS. The variant could modify the formation of multichannel protein complexes, affecting ion channels to specific compartments in cardiomyocytes.