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Objective Megalencephalic leukoencephalopathy with subcortical cysts (MLC, MIM＃ 604004) is an autosomal recessively inherited disease resulting from a deficiency of MLCl protein. This study was to identify MLCl mutations and perform their functional studies in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC). Methods The analysis of clinical features and MLCl mutation screening were performed in 13 Chinese patients. The functional study of MLC1 variants was carried out by western blot, real-time PCR and confocal microscope. U373MG cells transfected by p.cDNA3.1-HA-MLC1 wildtype and mutants were immunoassayed with antibodies of HA and calnexin, an HR marker. Results A total of 10 MLCl mutations were identified in these patients, including five novel missense mutations (c.65G>A, p.R22Q; c.95C>T, p.A32V; c.218G>A, p.G73E; c.823G>A, p.A275T; c.832T>C, p.Y278H), one novel splicing mutation (c.772-lG>C in IVS9-1), one novel small deletion (c.907_930del, p.V3O3_L31Odel), one known nonsense mutation (c.593delCTCA, p.Y198X) and two known missense mutations (C.206OT, p.S69L; c.353C>T, p.Tl 18M).