Kwok Sit Yee, Kwong Anna Ka Yee, Shi Julia Zhuo, Shih Connie Fong Ying, Lee Mianne, Mak Christopher C Y, Chui Martin, Tsao Sabrina, Chung Brian Hon Yin
Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong, Hong Kong SAR, China.
Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China.
Front Cardiovasc Med. 2024 Mar 20;11:1335527. doi: 10.3389/fcvm.2024.1335527. eCollection 2024.
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.
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.
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 (Barth syndrome), a variant of unknown significance (VUS) in and 2 compound heterozygous LP variants in ( and ) 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.
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.
在过去几年中，儿科心脏通道病和心肌病的精准医学取得了快速进展。与传统的基因panel和外显子组检测相比，全基因组测序（WGS）在启动子、内含子区域和线粒体基因组方面提供了额外的覆盖范围。然而，关于使用WGS评估儿童和青少年这些心血管疾病遗传病因的数据有限。
在一家三级儿科心脏病中心，我们招募了所有年龄在0至18岁之间被诊断为心脏通道病和心肌病的患者，这些患者先前进行基因panel或外显子组检测时遗传结果为阴性。经过遗传咨询后，采集了受试者及其父母的血样进行WGS分析。
共招募了31例患者（11例心脏通道病和20例心肌病）。在3例心肌病患者中鉴定出4个内含子剪接位点变异，这些变异在先前的全外显子组测序中未被发现。其中包括1例患有Barth综合征的患者中的1个致病变异、1例意义未明的变异（VUS）以及1例具有RASopathy临床特征患者中的2个复合杂合LP变异（和）。除了传统基因检测外，使用WGS鉴定内含子变异的额外诊断率为1.94%。
WGS在识别孤立性心肌病儿科患者中额外的内含子剪接位点变异方面发挥了作用。尽管WGS能够提供潜在的临床重要信息，但其额外检出率较低，因此应以具有成本效益的方式在选定的儿科心脏通道病和心肌病病例中考虑使用WGS。
