Jing Siyuan, Liu Lu, Li Yifei, Liu Fuqiang, Hua Yimin, Duan Hongyu
Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
Front Cardiovasc Med. 2024 Oct 11;11:1469237. doi: 10.3389/fcvm.2024.1469237. eCollection 2024.
The (choline kinase beta) gene plays a crucial role in regulating mitochondrial function and choline metabolism. Mutations in lead to conditions such as megaconial congenital muscular dystrophy (MCMD), characterized by enlarged mitochondria and impaired mitochondrial function, inducing various clinical features in neurological and cardiac performance. Herein, we report a rare case presenting with dilated cardiomyopathy as the dominant feature with a homozygous nonsense variant of and the related therapeutic strategy.
The proband, a 13-year-old male, presented with a complex clinical profile characterized by mild intellectual disability and severe cardiac impairment, including reduced activity tolerance, suspected acute heart failure, significant cardiac enlargement, a left anterior fascicular block, and a complete right bundle branch block. Whole exome sequencing (WES) identified a homozygous nonsense variant, c.598delC (p.Q200Rfs11) of the gene, that resulted in disease caused by amino acid sequence changes, a truncated protein, and splice site changes, as demonstrated by MutationTaster analysis. The protein structure of CHKB was built and named AF-Q9Y259-F1. The residue around 200 amino acid sites changed in CHKB p.Q200Rfs11 with unaltered hydrogen bonds which indicated the pathogenicity of the variant mainly originated from a truncated protein induced by the nonsense mutation. The heart blocks in the proband were considered to be associated with choline metabolic impairment, and thus cardiac resynchronization therapy would benefit the patient. Furthermore, the missense homozygous or compound heterozygous variants of as well as the combined compound heterozygous missense and nonsense variants of usually lead to neurological impairments and muscular weakness.
This study expands the spectrum of mutations and provides essential information for the genotype-phenotype map of a nonsense variant of the gene. It is important to confirm a differential diagnosis among such patients using WES analyses. Regular cardiac and musculoskeletal monitoring is recommended for MCMD patients. Patients with a CHKB deficiency presenting with heart blocks could benefit from the administration of cardiac resynchronization therapy. This therapeutic approach might improve cardiac function and conduction in patients with CHKB-related cardiomyopathies.
胆碱激酶β（CHKB）基因在调节线粒体功能和胆碱代谢中起关键作用。CHKB基因突变会导致诸如大嵴先天性肌营养不良（MCMD）等病症，其特征为线粒体增大和线粒体功能受损，进而在神经和心脏功能方面引发各种临床症状。在此，我们报告一例以扩张型心肌病为主要特征的罕见病例，该病例存在CHKB基因纯合无义变异及相关治疗策略。
先证者为一名13岁男性，临床表现复杂，有轻度智力障碍和严重心脏损害，包括活动耐力下降、疑似急性心力衰竭、明显心脏扩大、左前分支阻滞和完全性右束支阻滞。全外显子组测序（WES）鉴定出CHKB基因的一个纯合无义变异，即c.598delC（p.Q200Rfs11），MutationTaster分析表明该变异导致了由氨基酸序列改变、截短蛋白和剪接位点改变引起的疾病。构建了CHKB的蛋白质结构并命名为AF-Q9Y259-F1。CHKB p.Q200Rfs11中约200个氨基酸位点周围的残基发生了变化，氢键未改变，这表明该变异的致病性主要源于无义突变诱导的截短蛋白。先证者的心脏传导阻滞被认为与胆碱代谢受损有关，因此心脏再同步治疗可能对患者有益。此外，CHKB的错义纯合或复合杂合变异以及CHKB与其他基因的复合杂合错义与无义变异组合通常会导致神经功能障碍和肌肉无力。
本研究扩展了CHKB基因突变谱，并为该基因无义变异的基因型-表型图谱提供了重要信息。使用WES分析对这类患者进行鉴别诊断很重要。建议对MCMD患者进行定期心脏和肌肉骨骼监测。出现心脏传导阻滞的CHKB缺乏患者可能从心脏再同步治疗中获益。这种治疗方法可能改善CHKB相关心肌病患者的心脏功能和传导。
