Open AccessNovel de novo POLR3B mutations responsible for demyelinating Charcot–Marie–Tooth disease in Japan
Author(s) -
Ando Masahiro,
Higuchi Yujiro,
Yuan JunHui,
Yoshimura Akiko,
Kitao Ruriko,
Morimoto Takehiko,
Taniguchi Takaki,
Takeuchi Mika,
Takei Jun,
Hiramatsu Yu,
Sakiyama Yusuke,
Hashiguchi Akihiro,
Okamoto Yuji,
Mitsui Jun,
Ishiura Hiroyuki,
Tsuji Shoji,
Takashima Hiroshi
Publication year - 2022
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.51555
Subject(s) - medicine , missense mutation , exome sequencing , spasticity , compound heterozygosity , ataxia , mutation , cerebellar ataxia , genetics , pathology , gene , biology , psychiatry , physical therapy
Abstract Background Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. Methods We performed whole‐exome sequencing (WES) of DNA samples from 804 Charcot–Marie–Tooth (CMT) cases that could not be genetically diagnosed by DNA‐targeted resequencing microarray using next‐generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. Results We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early‐onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. Conclusion Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT‐related gene panel for comprehensive genetic screening, particularly for patients with early‐onset demyelinating CMT.