Hypomyelinating disorders in China: The clinical and genetic heterogeneity in 119 patients.

Haoran Ji,Jiangxi Xiao,Huijuan Li,Ye Wu,Jingmin Wang,Yanling Yang,Han Xie,Li Li,Lu Zhao,Zhengping Niu,Zhixian Yang,Haijuan Zhao,Yuehua Zhang,Xingzhi Chang,Jinhua Ji,Liping Kou,Xinhua Bao,Taoyun Ji,Hui Xiong,Yuwu Jiang,Quanli Zhang,Ming Li,Dongxiao Li,Xiru Wu,Hongchun Feng,Hong Wang ,Qing Gu

doi:10.1371/journal.pone.0188869

Abstract

ObjectiveHypomyelinating 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.Methods119 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.ResultsClinical 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.SignificanceThis 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.

Highlights

Hypomyelinating disorders (HMDs) are a spectrum of genetic disorders with deficiency in the process of myelination, characterized by a persistent high intensity T2 signal coupled with a mildly hypo, iso, or high intensity T1 signal in white matter of an MRI scan[1]
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%)
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

Summary

Introduction

Hypomyelinating disorders (HMDs) are a spectrum of genetic disorders with deficiency in the process of myelination, characterized by a persistent high intensity T2 signal coupled with a mildly hypo-, iso-, or high intensity T1 signal in white matter of an MRI scan[1]. Nystagmus and developmental delay often occur in the neonatal or infantile period, and hypotonia, spasticity, extrapyramidal signs, ataxia, or seizures may be present. Both X-linked and autosomal recessive/dominant gene mutations are identified responsible. The hypomyelination pattern was first defined in 2009, and MRI and generation sequencing were reported important tools for identifying HMDs [3, 5, 6]. Seldom general analysis on HMDs was reported except one in 2014 [2], and more reports were needed to illuminate the HLDs features, especially in Chinese population without analysis yet. We examine 119 Chinese patients with HMDs to elucidate the clinical and genetic features of HMDs in Chinese population, and to facilitate correct genetic consulting and prenatal diagnosis for the families affected

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