Targeted exome sequencing for mitochondrial disorders reveals high genetic heterogeneity.
Targeted exome sequencing for mitochondrial disorders reveals high genetic heterogeneity.
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DOI：
10.1186/1471-2350-14-118
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发表时间：
2013-11-11
影响因子：
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通讯作者：
Hahn SH
中科院分区：
文献类型：
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作者：
DaRe JT;Vasta V;Penn J;Tran NT;Hahn SH
由于极端的遗传和表型异质性，线粒体疾病很难诊断。我们在148名提交临床测试的患者中探索了靶向下一代测序在线粒体疾病诊断中的作用。测试了一组447个编码线粒体呼吸链复合体的核基因，以及其他导致继发性线粒体功能障碍或导致类似线粒体疾病的疾病的基因。我们根据家庭隔离数据确定了被认为可能致病的变异和/或已知在13名患者的12个基因中致病的变异。在另外45个基因中发现了罕见的或新的未知意义的变异，这些基因与各种代谢、遗传或神经遗传学疾病有关。只有4名患者证实了原发线粒体缺陷，这表明大多数疑似线粒体疾病的患者可能不是能量产生的直接损害的结果。我们的结果支持线粒体疾病的临床和常规实验室确认是具有挑战性的，因为显著重叠的非特异性临床症状和缺乏特定的生物标记物。虽然下一代测序显示出诊断可疑线粒体疾病的希望，但挑战仍然存在，因为潜在的遗传异质性可能比想象的更大，而且症状与我们这里报告的其他疾病的相似性进一步混淆了这一点。
Mitochondrial disorders are difficult to diagnose due to extreme genetic and phenotypic heterogeneities. We explored the utility of targeted next-generation sequencing for the diagnosis of mitochondrial disorders in 148 patients submitted for clinical testing. A panel of 447 nuclear genes encoding mitochondrial respiratory chain complexes, and other genes inducing secondary mitochondrial dysfunction or that cause diseases which mimic mitochondrial disorders were tested. We identified variants considered to be possibly disease-causing based on family segregation data and/or variants already known to cause disease in twelve genes in thirteen patients. Rare or novel variants of unknown significance were identified in 45 additional genes for various metabolic, genetic or neurogenetic disorders. Primary mitochondrial defects were confirmed only in four patients indicating that majority of patients with suspected mitochondrial disorders are presumably not the result of direct impairment of energy production. Our results support that clinical and routine laboratory ascertainment for mitochondrial disorders are challenging due to significant overlapping non-specific clinical symptoms and lack of specific biomarkers. While next-generation sequencing shows promise for diagnosing suspected mitochondrial disorders, the challenges remain as the underlying genetic heterogeneity may be greater than suspected and it is further confounded by the similarity of symptoms with other conditions as we report here.