Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing.
Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing.
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DOI：
10.1126/scitranslmed.3003310
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发表时间：
2012-01-25
影响因子：
17.1
通讯作者：
Mootha VK
中科院分区：
文献类型：
--
作者：
Calvo SE;Compton AG;Hershman SG;Lim SC;Lieber DS;Tucker EJ;Laskowski A;Garone C;Liu S;Jaffe DB;Christodoulou J;Fletcher JM;Bruno DL;Goldblatt J;Dimauro S;Thorburn DR;Mootha VK
下一代测序（NGS）的进展有望促进遗传性疾病的诊断。虽然在研究环境中，NGS已经在大家庭中使用分离来精确定位致病等位基因，但临床诊断的关键挑战是应用于单个个体。为了探索其诊断效用，我们对42名具有线粒体氧化磷酸化疾病临床和生化证据的不相关婴儿进行了靶向NGS，这些婴儿难以进行传统的分子诊断。这些破坏性的线粒体疾病的特征是表型和遗传异质性，迄今已鉴定出100多个致病基因。我们对线粒体DNA（mtDNA）和编码线粒体蛋白的约1000个核基因的外显子进行了“MitoExome”测序，并优先考虑了预测会破坏功能的罕见突变。由于患者和对照组具有相当数量的杂合等位基因，我们不能优先考虑显性作用基因。然而，患者表现出五倍的基因富集，其中两个这样的突变可能是隐性疾病的基础。总共有23/42（55%）例患者携带这种隐性基因或致病性mtDNA变异体。在10名患者（24%）中进行了明确的诊断，这些患者先前与疾病相关的基因突变。13名患者（31%）的核基因突变与疾病无关。两个这样的基因，NDUFB 3和AGK的致病性分别由cDNA互补和来自多个患者的证据支持。结果强调了在临床环境中部署NGS的直接潜力和挑战。
Advances in next-generation sequencing (NGS) promise to facilitate diagnosis of inherited disorders. While in research settings NGS has pinpointed causal alleles using segregation in large families, the key challenge for clinical diagnosis is application to single individuals. To explore its diagnostic utility, we performed targeted NGS in 42 unrelated infants with clinical and biochemical evidence of mitochondrial oxidative phosphorylation disease, who were refractory to traditional molecular diagnosis. These devastating mitochondrial disorders are characterized by phenotypic and genetic heterogeneity, with over 100 causal genes identified to date. We performed “MitoExome” sequencing of the mitochondrial DNA (mtDNA) and exons of ~1000 nuclear genes encoding mitochondrial proteins and prioritized rare mutations predicted to disrupt function. Since patients and controls harbored a comparable number of such heterozygous alleles, we could not prioritize dominant acting genes. However, patients showed a five-fold enrichment of genes with two such mutations that could underlie recessive disease. In total, 23/42 (55%) patients harbored such recessive genes or pathogenic mtDNA variants. Firm diagnoses were enabled in 10 patients (24%) who had mutations in genes previously linked to disease. 13 patients (31%) had mutations in nuclear genes never linked to disease. The pathogenicity of two such genes, NDUFB3 and AGK, was supported by cDNA complementation and evidence from multiple patients, respectively. The results underscore the immediate potential and challenges of deploying NGS in clinical settings.
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DOI：
10.1083/jcb.200407123
发表时间：
2005-06-06
期刊：
The Journal of cell biology
影响因子：
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作者：
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通讯作者：
Spiegel S
影响因子：
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作者：
Bernier, FP;Boneh, A;Thorburn, DR
通讯作者：
Thorburn, DR
影响因子：
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通讯作者：
Nusbaum C
影响因子：
3.9
作者：
Bruno, Damien L.;Stark, Zornitza;Slater, Howard R.
通讯作者：
Slater, Howard R.
DOI：
10.1002/ajmg.1426
发表时间：
2001-03-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
Chinnery, PF;Turnbull, DM
通讯作者：
Turnbull, DM