LAUSR

OBJECTIVE Leukoencephalopathies are a group of heterogeneous disorders characterized by the degeneration of white matter, resulting in a variety of progressive neurological symptoms. To date, over 60 genes linked to genetic leukoencephalopathies have been discovered through whole-exome sequencing (WES) and long-read sequencing. Nonetheless, the genetic diversity and clinical variability of these disorders among various racial groups remain largely unknown. Therefore, this study aims to analyze the genetic spectrum and clinical features of Chinese adult leukoencephalopathies and compare the genetic profiles in different populations. METHODS A total of 129 patients suspected of possible genetic leukoencephalopathy were enrolled and underwent WES and dynamic mutation analysis. Bioinformatics tools were used to predict the pathogenicity of these mutations. Skin biopsies were conducted for further diagnosis. Genetic data sources from different populations were collected from published articles. RESULTS Genetic diagnosis was established in 48.1% of patients, with WES identifying 57 pathogenic or likely pathogenic variants in 39.5% of cases. NOTCH3 and NOTCH2NLC were the most common mutated genes, accounting for 12.4% and 8.5% of cases, respectively. Dynamic mutation analysis revealed NOTCH2NLC GGC repeat expansions in 8.5% of patients. Different mutations resulted in varying clinical symptoms and imaging findings. Comparisons of genetic profiles between different populations showed distinct mutational spectrums in adult leukoencephalopathies. INTERPRETATION This study highlights the importance of genetic testing for accurate diagnosis and improved clinical management of these disorders. It also sheds light on the genetic heterogeneity of adult leukoencephalopathies across different races, emphasizing the need for further research on this topic.