Hu Chaoping, Li Xihua, Zhao Lei, Shi Yiyun, Zhou Shuizhen, Wu Bingbing, Wang Yi
Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.
Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.
Eur J Med Genet. 2020 Aug;63(8):103898. doi: 10.1016/j.ejmg.2020.103898. Epub 2020 Apr 26.
Mitochondrial disorders (MDs) are genetic ailments affecting all age groups. Epidemiological data and frequencies of gene mutations in pediatric patients in China are scarce. This retrospective study assessed 101 patients with suspected MDs treated at the Neurology Department of Children's Hospital, Fudan University, in 2011-2017. Mitochondrial (mtDNA) and nuclear (nDNA) samples were assessed by long-range polymerase chain reaction (PCR)-based whole mtDNA sequencing and whole exome sequencing (WES) for identifying pathogenic mutations. Muscle samples underwent various staining protocols and immunofluorescence for detecting selected proteins. Seventeen mutations in the MT-TL1, MT-COX2, MT-ND4, MT, tRNA TRNE, MT-TN, MT-TK, MT-ATP6, MT-ND6, MT-ND3 and MT-CO3 genes were identified in 39 patients, of which m.3243A > G, m.3303C > T, m.8993T > C/G, m.9176T > C, and m.10191T > C were most common. Mitochondrial myopathy and MELAS were most common for m.3243A > G mutation. Four novel mutations were detected, including m.9478insT, m.5666T > C, m.8265T > C, and m.8380-13600 deletion mutations related to Leigh syndrome, mitochondrial myopathy and KSS, respectively. Thirty-three mutations in the TK2, POLG, IBA57, HADHB, FBXL4, ALDH5A1, FOXRED1, TPK1, NDUFAF5, NDUFAF7, NDUFV1, CARS2, PDHA1, and HIBCH genes were identified in 19 patients, including 23 currently unknown. Higher rates of TK2, POLG, IBA57, and HADHB mutations were found in nDNA-mutated MD compared with the remaining individuals. Besides, IBA57 c.286T > C (p.Y96H), TK2 c.497A > T (p.D166V) founder mutations critically contributed to MDs. Comprehensive genomic analysis plays a critical role in pediatric MD diagnosis. These data summarize the relative frequencies of different gene mutations in a large Chinese population, and identified 23 novel MD-associated nDNA and 4 novel mtDNA mutations.
线粒体疾病（MDs）是影响所有年龄组的遗传性疾病。中国儿科患者的流行病学数据和基因突变频率稀缺。这项回顾性研究评估了2011年至2017年在复旦大学附属儿科医院神经科接受治疗的101例疑似MDs患者。通过基于长距离聚合酶链反应（PCR）的全线粒体DNA测序和全外显子组测序（WES）对线粒体（mtDNA）和核（nDNA）样本进行评估，以识别致病突变。肌肉样本进行了各种染色方案和免疫荧光检测以检测选定的蛋白质。在39例患者中鉴定出MT-TL1、MT-COX2、MT-ND4、MT、tRNA TRNE、MT-TN、MT-TK、MT-ATP6、MT-ND6、MT-ND3和MT-CO3基因的17种突变，其中m.3243A＞G、m.3303C＞T、m.8993T＞C/G、m.9176T＞C和m.10191T＞C最为常见。线粒体肌病和MELAS是m.3243A＞G突变最常见的表现。检测到4种新突变，包括分别与Leigh综合征、线粒体肌病和KSS相关的m.9478insT、m.5666T＞C、m.8265T＞C和m.8380-13600缺失突变。在19例患者中鉴定出TK2、POLG、IBA57、HADHB、FBXL4、ALDH5A1、FOXRED1、TPK1、NDUFAF5、NDUFAF7NDUFV1、CARS2、PDHA1和HIBCH基因的33种突变，其中23种目前未知。与其余个体相比，在nDNA突变的MD中发现TK2、POLG、IBA57和HADHB突变的发生率更高。此外，IBA57 c.286T＞C（p.Y96H）和TK c.497A＞T（p.D166V）这两种奠基者突变对MDs有重要影响。综合基因组分析在儿科MD诊断中起关键作用。这些数据总结了中国一大群人中不同基因突变的相对频率，并鉴定出23种与MD相关的新nDNA突变和4种新的mtDNA突变。
