FHL2基因变异致扩张型心肌病1例并文献回顾  

A case of dilated cardiomyopathy caused by FHL2 gene variant and a literature review

作　　者：于春蕊 贾丽娟 郝婵娟 左汴京 李巍 王芳洁[3] 郭俊 Yu Chunrui;Jia Lijuan;Hao Chanjuan;Zuo Bianjing;Li Wei;Wang Fangjie;Guo Jun(Beijing Key Laboratory for Genetics of Birth Defects,Beijing Pediatric Research Institute MOE Key Laboratory of Major Diseases in Children Genetics and Birth Defects Control Center,Beijing Children′s Hospital,Capital Medical University,National Center for Children′s Health,Beijing 100045,China;Henan Provincial Key Laboratory of Pediatric Inherited&Metabolic Diseases,Henan Children′s Hospital,Zhengzhou Hospital of Beijing Children′s Hospital,Zhengzhou,Henan 450003,China;Department of Cardiology,Children′s Hospital Affiliated to Zhengzhou University,Henan Children′s Hospital,Zhengzhou Children′s Hospital,Zhengzhou,Henan 450003,China)

机构地区：[1]国家儿童医学中心,首都医科大学附属北京儿童医院,北京市儿科研究所出生缺陷遗传学研究室,儿科重大疾病研究教育部重点实验室,出生缺陷遗传学研究北京市重点实验室,北京100045 [2]北京儿童医院郑州医院,河南省儿童医院,河南省儿童遗传代谢病研究重点实验室,郑州450003 [3]郑州大学附属儿童医院,河南省儿童医院,郑州儿童医院心血管内科,郑州450003

出　　处：《中华医学遗传学杂志》2023年第3期337-343,共7页Chinese Journal of Medical Genetics

基　　金：国家科技部重点研发计划(2016YFC1000306);北京市科委医药协同科技创新研究项目(Z181100001918003);北京市首发基金(2018-2-1141);北京市卫生健康委公益发展改革试点项目(京医研2018-5)。

摘　　要：目的探讨1例扩张型心肌病(DCM)患儿的临床表型及遗传学特征。方法收集2020年4月28日就诊于郑州儿童医院的1例患儿的临床资料,并对其进行家系全外显子组测序(trio-WES),对候选变异进行Sanger测序验证。以"FHL2"作为关键词,检索1997年1月1日至2021年10月31日PubMed数据库收录的文献,同时在ClinVar数据库中检索FHL2变异作为补充支持,分析基因变异与临床特征的对应关系。结果患儿为女性,就诊时为5月龄,临床特征为左心室增大、收缩功能减低。基因测序发现其FHL2基因存在杂合错义变异c.391C>T(p.Arg131Cys),其父母未携带相同的变异。根据美国医学遗传学与基因组学学会(ACMG)变异相关指南,c.391C>T(p.Arg131Cys)被升级为可能致病性变异(PS2+PM2_Supporting+PP3+PP5)。通过文献检索,共发现10例FHL2基因变异的患者,其中6例表现为DCM,2例表现为肥厚型心肌病(HCM),2例表现为不明原因猝死(SUD)。变异位于FHL2蛋白LIM 3结构域的患者均表现为HCM,位于LIM 0~2、LIM 4结构域者则主要表现为DCM。结论FHL2基因杂合错义变异c.391C>T(p.Arg131Cys)可能是患儿DCM的原因。上述发现强调了trio-WES在疾病诊断和遗传咨询中的重要性。Objective To explore the clinical phenotype and genetic features of a child with dilated cardiomyopathy(DCM).Methods Clinical data of the child who had presented at Zhengzhou Children′s Hospital on April 28,2020 was collected.Trio-whole exome sequencing(trio-WES)was carried out for the child and her parents,and candidate variants were validated by Sanger sequencing."FHL2"was taken as the key word to retrieve related literature from January 1,1997 to October 31,2021 in the PubMed database and was also searched in the ClinVar database as a supplement to analyze the correlation between genetic variants and clinical features.Results The patient was a 5-month-old female infant presented with left ventricular enlargement and reduced systolic function.A heterozygous missense variant c.391C>T(p.Arg131Cys)in FHL2 gene was identified through trio-WES.The same variant was not detected in either of her parents.A total of ten patients with FHL2 gene variants have been reported by previous literature,six of them presented with DCM,two with hypertrophic cardiomyopathy(HCM),and two with sudden unexplained death(SUD).Phenotypic analysis revealed that patients with variants in the LIM 3 domain presented hypertrophic cardiomyopathy and those with variants of the LIM 0~2 and LIM 4 domains had mainly presented DCM.The c.391C>T(p.Arg131Cys)has been identified in a child with DCM,though this variant has not been validated among the patient′s family members.Based on the guidelines of the American College of Medical Genetics and Genomics,the c.391C>T(p.Arg131Cys)variant was re-classified as likely pathogenic(PS2+PM2_Supporting+PP3+PP5).Conclusion The heterozygous missense variant of c.391C>T(p.Arg131Cys)in the FHL2 gene probably predisposed to the DCM in this child,which has highlighted the importance of trio-WES in the clinical diagnosis and genetic counseling.

关 键 词：扩张型心肌病 FHL2基因 全外显子组测序 

分 类 号：R725.4[医药卫生—儿科]