PDF(Pubmed)
Abstract：
UNASSIGNED: Precision medicine in paediatric cardiac channelopathy and cardiomyopathy has a rapid advancement over the past years. Compared to conventional gene panel and exome-based testing, whole genome sequencing (WGS) offers additional coverage at the promoter, intronic regions and the mitochondrial genome. However, the data on use of WGS to evaluate the genetic cause of these cardiovascular conditions in children and adolescents are limited.
UNASSIGNED: In a tertiary paediatric cardiology center, we recruited all patients diagnosed with cardiac channelopathy and cardiomyopathy between the ages of 0 and 18 years old, who had negative genetic findings with prior gene panel or exome-based testing. After genetic counselling, blood samples were collected from the subjects and both their parents for WGS analysis.
UNASSIGNED: A total of 31 patients (11 cardiac channelopathy and 20 cardiomyopathy) were recruited. Four intronic splice-site variants were identified in three cardiomyopathy patients, which were not identified in previous whole exome sequencing. These included a pathogenic variant in TAFAZZIN:c.284+5G>A (Barth syndrome), a variant of unknown significance (VUS) in MYBPC3:c.1224-80G>A and 2 compound heterozygous LP variants in LZTR1 (LZTR1:c.1943-256C>T and LZTR1:c1261-3C>G) in a patient with clinical features of RASopathy. There was an additional diagnostic yield of 1.94% using WGS for identification of intronic variants, on top of conventional gene testing.
UNASSIGNED: WGS plays a role in identifying additional intronic splice-site variants in paediatric patients with isolated cardiomyopathy. With the demonstrated low extra yield of WGS albeit its ability to provide potential clinically important information, WGS should be considered in selected paediatric cases of cardiac channelopathy and cardiomyopathy in a cost-effective manner.
UNASSIGNED: In a tertiary paediatric cardiology center, we recruited all patients diagnosed with cardiac channelopathy and cardiomyopathy between the ages of 0 and 18 years old, who had negative genetic findings with prior gene panel or exome-based testing. After genetic counselling, blood samples were collected from the subjects and both their parents for WGS analysis.
UNASSIGNED: A total of 31 patients (11 cardiac channelopathy and 20 cardiomyopathy) were recruited. Four intronic splice-site variants were identified in three cardiomyopathy patients, which were not identified in previous whole exome sequencing. These included a pathogenic variant in TAFAZZIN:c.284+5G>A (Barth syndrome), a variant of unknown significance (VUS) in MYBPC3:c.1224-80G>A and 2 compound heterozygous LP variants in LZTR1 (LZTR1:c.1943-256C>T and LZTR1:c1261-3C>G) in a patient with clinical features of RASopathy. There was an additional diagnostic yield of 1.94% using WGS for identification of intronic variants, on top of conventional gene testing.
UNASSIGNED: WGS plays a role in identifying additional intronic splice-site variants in paediatric patients with isolated cardiomyopathy. With the demonstrated low extra yield of WGS albeit its ability to provide potential clinically important information, WGS should be considered in selected paediatric cases of cardiac channelopathy and cardiomyopathy in a cost-effective manner.
摘要：
■在过去的几年中，儿科心血管疾病和心肌病的精准医学有了迅速的发展。与传统的基因面板和基于外显子组的测试相比，全基因组测序（WGS）在启动子处提供了额外的覆盖，内含子区域和线粒体基因组。然而,使用WGS评估儿童和青少年心血管疾病的遗传原因的数据有限.
■在三级儿科心脏病中心，我们招募了所有被诊断为0至18岁之间的心血管病和心肌病的患者，先前的基因组研究或基于外显子组的检测结果为阴性。遗传咨询后，从受试者及其父母双方收集血样进行WGS分析.
■共招募了31例患者（11例心脑血管疾病和20例心肌病）。在三名心肌病患者中发现了四种内含子剪接位点变异，在以前的全外显子组测序中未发现。这些包括TAFAZZIN的致病性变异：c.284+5G>A（Barth综合征），MYBPC3中的一个未知意义的变异体(VUS):c.1224-80G>A和LZTR1中的2个复合杂合LP变异体(LZTR1:c.1943-256C>T和LZTR1:c1261-3C>G)。使用WGS鉴定内含子变异有1.94%的额外诊断率，在常规基因检测的基础上.
■WGS在确定患有孤立性心肌病的儿科患者的其他内含子剪接位点变异中起作用。尽管WGS具有提供潜在临床重要信息的能力，但证明了WGS的低额外产量，在选定的心血管疾病和心肌病儿科病例中，应以经济有效的方式考虑WGS。
■在三级儿科心脏病中心，我们招募了所有被诊断为0至18岁之间的心血管病和心肌病的患者，先前的基因组研究或基于外显子组的检测结果为阴性。遗传咨询后，从受试者及其父母双方收集血样进行WGS分析.
■共招募了31例患者（11例心脑血管疾病和20例心肌病）。在三名心肌病患者中发现了四种内含子剪接位点变异，在以前的全外显子组测序中未发现。这些包括TAFAZZIN的致病性变异：c.284+5G>A（Barth综合征），MYBPC3中的一个未知意义的变异体(VUS):c.1224-80G>A和LZTR1中的2个复合杂合LP变异体(LZTR1:c.1943-256C>T和LZTR1:c1261-3C>G)。使用WGS鉴定内含子变异有1.94%的额外诊断率，在常规基因检测的基础上.
■WGS在确定患有孤立性心肌病的儿科患者的其他内含子剪接位点变异中起作用。尽管WGS具有提供潜在临床重要信息的能力，但证明了WGS的低额外产量，在选定的心血管疾病和心肌病儿科病例中，应以经济有效的方式考虑WGS。
