Ji Haoran, Li Dongxiao, Wu Ye, Zhang Quanli, Gu Qiang, Xie Han, Ji Taoyun, Wang Huifang, Zhao Lu, Zhao Haijuan, Yang Yanling, Feng Hongchun, Xiong Hui, Ji Jinhua, Yang Zhixian, Kou Liping, Li Ming, Bao Xinhua, Chang Xingzhi, Zhang Yuehua, Li Li, Li Huijuan, Niu Zhengping, Wu Xiru, Xiao Jiangxi, Jiang Yuwu, Wang Jingmin
Department of Pediatrics, Peking University First Hospital, Beijing, China.
Department of Radiology, Peking University First Hospital, Beijing, China.
PLoS One. 2018 Feb 16;13(2):e0188869. doi: 10.1371/journal.pone.0188869. eCollection 2018.
Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on brain MRI scans. This study was aimed to clarify the clinical and genetic features of HMDs in Chinese population.
119 patients with hypomyelinating disorders in Chinese population were enrolled and evaluated based on their history, clinical manifestation, laboratory examinations, series of brain MRI with follow-up, genetic etiological tests including chromosomal analysis, multiplex ligation probe amplification, Sanger sequencing, targeted enrichment-based next-generation sequencing and whole exome sequencing.
Clinical and genetic features of hypomyelinating disorders were revealed. Nine different hypomyelinating disorders were identified in 119 patients: Pelizaeus-Merzbacher disease (94, 79%), Pelizaeus-Merzbacher-like disease (10, 8%), hypomyelination with atrophy of the basal ganglia and cerebellum (3, 3%), GM1 gangliosidosis (5, 4%), GM2 gangliosidosis (3, 3%), trichothiodystrophy (1, 1%), Pol III-related leukodystrophy (1, 1%), hypomyelinating leukodystrophy type 9 (1, 1%), and chromosome 18q deletion syndrome (1, 1%). Of the sample, 94% (112/119) of the patients were genetically diagnosed, including 111 with mutations distributing across 9 genes including PLP1, GJC2, TUBB4A, GLB1, HEXA, HEXB, ERCC2, POLR3A, and RARS and 1 with mosaic chromosomal change of 46, XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18. Eighteen novel mutations were discovered. Mutations in POLR3A and RARS were first identified in Chinese patients with Pol III-related leukodystrophy and hypomyelinating leukodystrophy, respectively.
This is the first report on clinical and genetic features of hypomyelinating disorders with a large sample of patients in Chinese population, identifying 18 novel mutations especially mutations in POLR3A and RARS in Chinese patients, expanding clinical and genetic spectrums of hypomyelinating disorders.
低髓鞘形成障碍是一组临床和遗传异质性疾病，其特征为神经功能恶化，脑部磁共振成像（MRI）扫描可见髓鞘形成减少。本研究旨在阐明中国人群中低髓鞘形成障碍的临床和遗传特征。
纳入119例中国人群中的低髓鞘形成障碍患者，根据其病史、临床表现、实验室检查、系列脑部MRI及随访、包括染色体分析、多重连接探针扩增、桑格测序、靶向富集二代测序和全外显子测序在内的遗传病因检测进行评估。
揭示了低髓鞘形成障碍的临床和遗传特征。在119例患者中鉴定出9种不同的低髓鞘形成障碍：佩利措伊斯-梅茨巴赫病（94例，79%）、佩利措伊斯-梅茨巴赫样病（10例，8%）、基底节和小脑萎缩伴髓鞘形成减少（3例，3%）、GM1神经节苷脂贮积症（5例，4%）、GM2神经节苷脂贮积症（3例，3%）、毛发硫营养不良（1例，1%）、与RNA聚合酶III相关的脑白质营养不良（1例，1%）、9型低髓鞘性脑白质营养不良（1例，1%）和18号染色体q缺失综合征（1例，1%）。在该样本中，94%（11 /119）的患者得到了基因诊断，其中111例患者有分布于9个基因（包括PLP1、GJC2、TUBB4A、GLB1、HEXA、HEXB、ERCC2、POLR3A和RARS）的突变，1例患者有46, XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18的嵌合染色体改变。发现了18个新突变。POLR3A和RARS的突变分别首次在中国与RNA聚合酶III相关的脑白质营养不良和低髓鞘性脑白质营养不良患者中鉴定出。
这是关于中国人群中大量低髓鞘形成障碍患者临床和遗传特征的首份报告，鉴定出18个新突变，尤其是中国患者中POLR3A和RARS的突变，扩展了低髓鞘形成障碍的临床和遗传谱。
