New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies

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.

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.

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.

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.