Identification of extremely rare mitochondrial disorders by whole exome sequencing
Identification of extremely rare mitochondrial disorders by whole exome sequencing
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DOI：
10.1038/s10038-019-0660-y
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发表时间：
2019-11-01
影响因子：
3.5
通讯作者：
Lee, Beom Hee
中科院分区：
文献类型：
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作者：
Seo, Go Hun;Oh, Arum;Lee, Beom Hee
全外显子组测序（WES）是一种有效的工具，用于遗传诊断线粒体疾病由于各种核遗传缺陷。在这项研究中，描述了三名受核遗传缺陷引起的极其罕见的线粒体疾病影响的患者。每例患者的医疗记录进行了审查，以获得临床症状，生化和影像学研究的结果，肌肉活检。对每例患者进行WES和全mtDNA大规模平行测序。测定耗氧率（OCR）和复合物活性I和IV。患者1和2从婴儿早期就表现出全面发育迟缓和癫痫发作。血乳酸、乳酸/丙酮酸比值和尿中克雷布斯循环中间产物排泄量显著升高。患者1还出现眼肌麻痹。患者2有左心室肥大和共济失调。患者3在29岁时出现构音障碍、步态障碍和右侧无力。脑磁共振成像显示异常信号强度，涉及双侧丘脑，中脑，或脑桥。基于WES，患者1在MTO 1中具有p.Glu415Gly和p.Arg484Trp变体。在患者2中，在TSFM中鉴定出p.Gln111ThrfsTer5和RNA错误剪接。患者3在AARS 2中携带p.Met151Thr和p.Met246Lys变体。3例患者皮肤成纤维细胞的OCR和复合物1活性降低，线粒体DNA正常。这些结果证明了WES用于识别极其罕见的线粒体疾病的遗传原因的实用性，这对遗传咨询有影响。
Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. WES and massive parallel sequencing of whole mtDNA were performed for each patient. The oxygen consumption rate (OCR) and complex activity I and IV was measured. Patients 1 and 2 had exhibited global developmental delay and seizure since early infancy. Blood lactate, the lactate-to-pyruvate ratio, and urinary excretion of Krebs cycle intermediates were markedly elevated. Patient 1 also was noted for ophthalmoplegia. Patient 2 had left ventricular hypertrophy and ataxia. Patient 3 developed dysarthria, gait disturbance, and right-side weakness at age 29. Brain magnetic resonance imaging demonstrated abnormal signal intensity involving the bilateral thalami, midbrain, or pons. Based on WES, patient 1 had p.Glu415Gly and p.Arg484Trp variants in MTO1 . In patient 2, p.Gln111ThrfsTer5 and RNA mis-splicing were identified in TSFM. Patient 3 carried p.Met151Thr and p.Met246Lys variants in AARS2. Skin fibroblasts of three patients exhibited decreased OCRs and complex 1 activity, and mitochondrial DNA was normal. These results demonstrate the utility of WES for identifying the genetic cause of extremely rare mitochondrial disorders, which has implications for genetic counseling.