NDUFS1基因复合杂合变异致线粒体呼吸链复合物Ⅰ缺陷一家系

Compound heterozygous NDUFS1 variants identified in a Chinese pedigree affected with mitochondrial respiratory chain complexⅠdeficiency

目的探讨1个疑似线粒体病家系的遗传学病因。方法收集患者及其家系成员的临床资料;抽取家系成员外周血,应用二代测序进行家系全外显子组、基因组拷贝数变异和线粒体基因组检测,对候选基因变异位点进行Sanger测序验证。结果全外显子组家系检测发现患儿存在NDUFS1基因父源c.64C>T(p.R22X)和母源c.845A>G(p.N282S)复合杂合变异,二者均可能导致蛋白功能丧失。基因组拷贝数变异和线粒体基因组检测未发现致病变异。结论疑似线粒体病的患儿可能缺少特异性的临床表型,包含线粒体DNA检测在内的综合性基因检测策略有助于及早明确诊断和治疗干预。

Objective To explore the genetic basis for a Chinese pedigree with suspected mitochondrial functional defects through combined next-generation sequencing(NGS),copy number variation sequencing(CNV-seq),and mitochondrial DNA(mtDNA)sequencing.Methods Clinical data of the proband and his family members were collected.The patient and his parents were subjected to family-trio whole-exome sequencing(WES),CNV-seq and mtDNA variant detection.Candidate variant was verified by Sanger sequencing.Results Trio-WES revealed that the proband has carried compound heterozygous variants of the NDUFS1 gene,including a paternally derived c.64C>T(p.R22X)nonsense variant and a maternally derived c.845A>G(p.N282S)missense variant.Both variants may cause loss of protein function.No variant that may cause the phenotype was identified by CNV-seq and mtDNA variant analysis.Conclusion Children with suspected mitochondrial disorders may have no specific syndromes or laboratory findings.A comprehensive strategy including mtDNA testing may facilitate the diagnosis and early clinical interventions.