RRM2B基因变异相关线粒体DNA耗竭综合征8B型一家系临床及遗传学分析

Clinical phenotype and genetic characteristics of a family with mitochondrial DNA depletion syndrome 8B caused by RRM2B gene mutation

目的分析RRM2B基因变异致线粒体DNA耗竭综合征8B型(MTDPS8B)一家系临床表型及遗传学特征。方法收集临沂市人民医院小儿神经内科2019年11月收治的一MTDPS8B家系资料。应用全外显子测序、线粒体环基因测序和Sanger测序法对患儿及其直系亲属进行基因检测,并对变异位点进行致病性分析和蛋白质3D建模,分析该家系成员的基因型和临床表型。结果该家系三代共8人,其中6人进行基因检测,4人存在8号染色体RRM2B基因c.627G>A(p.M209I)(NM_001172477)杂合变异,该位点高度保守且国内外多个权威数据库未见报道。蛋白质3D建模发现该变异可能影响蛋白质稳定性和功能。先证者及携带相同变异的两个姐姐均为MTDPS8B,表现为胃肠道功能障碍,运动功能及智力进行性倒退;母亲携带相同变异仅存在智力障碍;父亲及大姐未携带该变异且临床表型正常;外祖父母临床表型正常,因去世未行基因检测;变异与疾病在该家系中共分离。根据美国医学遗传学与基因组学学会变异分类标准与指南,判读为可能致病性变异(PM1+PM2+PP1+PP3)。结论c.627G>A变异可引发RRM2B基因相关疾病,且携带相同变异的家系成员临床严重程度可不相同。

ObjectiveTo investigate the clinical phenotype and genetic characteristics of a family with mitochondrial DNA depletion syndrome(MTDPS8B)caused by RRM2B gene mutation.MethodsData of a family with MTDPS8B admitted to Department of Pediatric Neurology,Linyi People's Hospital in November 2019 were collected.Whole exome sequencing,mitochondrial loop gene sequencing and Sanger sequencing were used for genetic test in the child and family members,and pathogenicity analysis and protein 3D modeling on the mutation sites were conducted.The clinical phenotype and genetic characteristics of the family members were summarized.ResultsSix subjects in these 8 individuals from the three generations of this family underwent genetic test.Four subjects had c.627G>A(p.M209I)(NM_001172477)heterozygous variation in RRM2B gene on the chromosome 8,and the variation was highly conserved;and no report on this variation has been found in domestic and foreign databases yet.Protein 3D modeling found that this variation may affect protein stability and function.The proband(male)and two older sisters carried the same variant had MTDPS8B,manifested as gastrointestinal dysfunction and progressive decline in motor function and intelligence,while the mother carried the same variant only had intellectual disability;the father and eldest sister did not carry the mutation and had normal clinical phenotype;the maternal grandparents had normal clinical phenotype and had passed away without genetic test;variation and disease were isolated in this family.The variation was interpreted as pathogenic(PM1+PM2+PP1+PP3)according to the American College of Medical Genetics and Genomics variant classification criteria and guidelines.ConclusionThe c.627G>A variant can cause RRM2B gene-related disease,and family members carried the same variants vary in clinical severity.