摘要
目的探讨1个原发性家族性脑钙化(PFBC)家系的临床特征及遗传学病因,分析MYORG基因变异在该家系中的致病机制。方法选取2024年5月13日因"发作性肢体抽搐1 d"就诊于浙江大学医学院附属第二医院的1例17岁女性患者为研究对象。对患者及其父母进行临床评估及影像学检查,采集外周血样本进行全外显子组测序(WES),筛选候选变异后通过Sanger测序验证,并依据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》(以下简称为"ACMG指南")进行致病性分析。本研究已通过浙江大学医学院附属第二医院医学伦理委员会的审查(批准号:预审研2020-674)。结果①患者表现为癫痫发作,头颅CT显示双侧基底节、小脑等多发钙化灶,总钙化评分为23分。②基因检测发现患者携带MYORG基因复合杂合变异:c.337348dup(p.Leu113Arg116dup)和c.1268T>G(p.Val423Gly),其中c.337348dup为已知致病性变异;家系共分离分析显示,患者父亲携带c.337348dup杂合变异,母亲携带c.1268T>G杂合变异。③根据ACMG指南,c.1268T>G被判定为可能致病性变异(PM2Supporting+PM3Supporting+PP1Supporting+PP3Moderate+PP4Supporting)。结论MYORG基因的新型复合杂合变异(c.337348dup和c.1268T>G)扩展了该基因的变异谱,进一步支持复合杂合变异是MYORG相关PFBC的重要遗传机制。
Objective To investigate the clinical characteristics and genetic etiology of a primary familial brain calcification(PFBC)family,and analyze the pathogenic mechanism of MYORG gene variants.Methods A 17-year-old female who presented to the Second Affiliated Hospital of Zhejiang University School of Medicine on 13 May 2024 with"paroxysmal limb twitching for 1 day"was enrolled.The patient and her parents underwent clinical evaluation and neuroimaging.Peripheral blood was collected for whole exome sequencing(WES).Candidate variants were confirmed by Sanger sequencing and interpreted using the American College of Medical Genetics and Genomics(ACMG)Standards and Guidelines for the Interpretation of Sequence Variants(hereinafter referred to as the ACMG Guidelines).This study was approved by Medical Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine(Ethics No.2020-674).Results①The patient experienced epileptic seizures.Cranial CT revealed multiple calcifications in the bilateral basal ganglia and cerebellum,with a total calcification score of 23.②WES identified compound heterozygous variants in MYORG:c.337_348dup(p.Leu113_Arg116dup),a known pathogenic variant,and c.1268T>G(p.Val423Gly).Segregation analysis showed that the father carried the c.337_348dup heterozygous variant,whereas the mother carried the c.1268T>G heterozygous variant.③According to ACMG guidelines,the c.1268T>G variant was classified as"likely pathogenic"(PM2_Supporting+PM3_Supporting+PP1_Supporting+PP3_Moderate+PP4_Supporting).Conclusion The novel compound heterozygous MYORG variants c.337_348dup and c.1268T>G have broadened the mutational spectrum of the MYORG gene and further supported compound heterozygosity as an important genetic mechanism in MYORG-related PFBC.
作者
夏恩奎
康怡欣
郑晓省
罗巍
Xia Enkui;Kang Yixin;Zheng Xiaosheng;Luo Wei(Department of Neurology,Zhoushan Third People's Hospital(Zhoushan Maternal and Child Health Hospital),Zhoushan,Zhejiang 316000,China;Department of Neurology,the Second Affiliated Hospital of Zhejiang University School of Medicine,Hangzhou,Zhejiang 310009,China)
出处
《中华医学遗传学杂志》
2025年第4期474-479,共6页
Chinese Journal of Medical Genetics
基金
浙江省"领雁"研发攻关计划(2024C03100)。
