AIM Leukodystrophies are a group of inherited white matter disorders with clinical, genetic, and imaging heterogeneity, which usually pose a diagnostic challenge for physicians. We aimed to identify new clinical characteristics and novel pathogenic variants of hereditary leukodystrophies in this study. METHODS Whole exome sequencing (WES) was performed in 28 unrelated patients clinically suspected with leukodystrophies. Leukocytes enzyme activity test, electroencephalogram (EEG), electromyography (EMG), and brain MRI were conducted. Functional analysis was performed, and the pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. RESULTS We made definite diagnosis in 8 probands with 12 pathogenic variants and reported new clinical characteristics and imaging features of these patients. Three novel pathogenic variants were identified, including a microdeletion variant c.2654_2654+3del within CSF1R, a nonsense variant c.1321C>T, and a missense variant c.166G>C within GALC. CONCLUSION Our results have deepened the understanding of clinical, genetic, and imaging heterogeneity of hereditary leukodystrophies, and expanded the spectrum of pathogenic variants and clinical features.

中文翻译：

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遗传性脑白质营养不良患者的新临床特征和新的致病变异。

AIM 脑白质营养不良是一组具有临床、遗传和影像异质性的遗传性白质疾病，通常给医生带来诊断挑战。在本研究中，我们旨在确定遗传性脑白质营养不良的新临床特征和新的致病变异。方法对 28 名临床怀疑患有脑白质营养不良的无关患者进行全外显子组测序 (WES)。进行了白细胞酶活性测试、脑电图（EEG）、肌电图（EMG）和脑部MRI。进行功能分析，并根据美国医学遗传学和基因组学学院（ACMG）标准和指南对变异的致病性进行分类。结果 我们对具有 12 个致病变异的 8 名先证者进行了明确诊断，并报告了这些患者的新的临床特征和影像学特征。鉴定了三种新的致病变异，包括 CSF1R 中的微缺失变异 c.2654_2654+3del、无义变异 c.1321C>T 和 GALC 中的错义变异 c.166G>C。结论 我们的研究结果加深了对遗传性脑白质营养不良的临床、遗传和影像异质性的理解，并扩大了致病变异和临床特征的范围。