Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, China.
Health Management Center, Third Xiangya Hospital, Central South University, Changsha, China.
Eur J Neurol. 2021 Nov;28(11):3774-3783. doi: 10.1111/ene.15024. Epub 2021 Jul 26.
The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot-Marie-Tooth disease (CMT) and related disorders from central south China.
In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation-dependent probe amplification for PMP22 duplication/deletion and CMT multi-gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis.
Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype.
Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.
本研究旨在提供中南地区一组遗传性运动感觉神经病（Charcot-Marie-Tooth disease，CMT）及相关疾病患者的基因型和表型分布概述。
共纳入 435 例患者，收集详细的临床资料。采用多重连接依赖性探针扩增技术（multiplex ligation-dependent probe amplification，MLPA）检测 PMP22 基因重复/缺失，采用 CMT 多基因panel 测序检测 CMT 相关基因。对未能明确分子诊断的患者进一步进行全外显子测序。
435 例患者中，216 例为 CMT1 型，14 例为遗传性神经病伴压力易损性（hereditary neuropathy with pressure palsies，HNPP），178 例为 CMT2 型，24 例为远端遗传性运动神经病（distal hereditary motor neuropathy，dHMN），3 例为遗传性感觉自主神经病（hereditary sensory and autonomic neuropathy，HSAN）。总体分子诊断率为 70%：CMT1 型为 75.7%，HNPP 型为 100%，CMT2 型为 64.6%，dHMN 型为 41.7%，HSAN 型为 33.3%。最常见的四种基因型占分子诊断患者的 68.9%。CMT1 型中较常见的病因是 PMP22 错义突变（4.6%）和 SH3TC2 突变（2.3%）；CMT2 型中较常见的病因是 GDAP1 突变（5.1%）、IGHMBP2 突变（4.5%）和 MORC2 突变（3.9%）。在 160 个检测到的致病性变异中，有 20 个与先前报道的表型相关，且其中 6 个基因的表型谱较宽，在 2 例散发性 CMT2 型患者中检测到 BAG3 和 SPTLC1 基因的致病性变异。
本研究结果提供了中南地区一组 CMT 及相关疾病患者独特的基因型和表型谱，包括相对较高比例的 CMT2 型和较低的 PMP22 重复发生率。某些基因的宽表型谱加深了我们对 CMT 的认识。
