Greiner Alexander M, Mehdi Haider, Cevan Chloe, Gutmann Rebecca, London Barry
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
Front Med (Lausanne). 2024 Jun 19;10:1159586. doi: 10.3389/fmed.2023.1159586. eCollection 2023.
Brugada Syndrome (BrS) is an inherited arrhythmia syndrome in which mutations in the cardiac sodium channel (Na1.5) account for approximately 20% of cases. Mutations in sodium channel-modifying genes may account for additional BrS cases, though BrS may be polygenic given common SNPs associated with BrS have been identified. Recent analysis, however, has suggested that should be regarded as the sole monogenic cause of BrS.
We sought to re-assess the genetic underpinnings of BrS in a large mutligenerational family with a putative mutation in that affects surface membrane expression of Na1.5 .
Fine linkage mapping was performed in the family using the Illumina Global Screening Array. Whole exome sequencing of the proband was performed to identify rare variants and mutations, and Sanger sequencing was used to assay previously-reported risk single nucleotide polymorphsims (SNPs) for BrS.
Linkage analysis decreased the size of the previously-reported microsatellite linkage region to approximately 3 Mb. GPD1L-A280V was the only coding non-synonymous variation present at less than 1% allele frequency in the proband within the linkage region. No rare non-synonymous variants were present outside the linkage area in affected individuals in genes associated with BrS. Risk SNPs known to predispose to BrS were overrepresented in affected members of the family.
Together, our data suggest GPD1L-A280V remains the most likely cause of BrS in this large multigenerational family. While care should be taken in interpreting variant pathogenicity given the genetic uncertainty of BrS, our data support inclusion of other putative BrS genes in clinical genetic panels.
布加综合征（BrS）是一种遗传性心律失常综合征，其中心脏钠通道（Na1.5）的突变约占病例的20%。钠通道修饰基因的突变可能导致更多的布加综合征病例，尽管鉴于已鉴定出与布加综合征相关的常见单核苷酸多态性（SNP），布加综合征可能是多基因的。然而，最近的分析表明，[此处原文缺失相关内容]应被视为布加综合征的唯一单基因病因。
我们试图在一个大型多代家族中重新评估布加综合征的遗传基础，该家族存在一个假定的[此处原文缺失相关内容]突变，该突变影响Na1.5的表面膜表达。
使用Illumina全球筛选阵列对该家族进行精细连锁图谱分析。对先证者进行全外显子组测序以鉴定罕见变异和突变，并使用桑格测序法检测先前报道的布加综合征风险单核苷酸多态性（SNP）。
连锁分析将先前报道的微卫星连锁区域的大小缩小至约3 Mb。GPD1L-A280V是连锁区域内先证者中唯一等位基因频率低于1%的编码非同义变异。在与布加综合征相关的基因中，受影响个体的连锁区域外不存在罕见的非同义变异。已知易患布加综合征的风险SNP在该家族的受影响成员中过度表达。
总之，我们的数据表明GPD1L-A280V仍然是这个大型多代家族中布加综合征最可能的病因。鉴于布加综合征的遗传不确定性，在解释变异致病性时应谨慎，但我们的数据支持在临床基因检测板中纳入其他假定的布加综合征基因。
