Lissencephaly is a developmental cortical malformation characterized by reduced to absent gyri and a disorganized cortex. Heterozygous mutations in the LIS1 gene, encoding a regulator of the microtubule-motor dynein, were identified to cause lissencephaly with different severities. While the clinical disease spectrum correlates with the degree of lissencephaly, location and type of mutation does not. Here we present forebrain-type organoids from LIS1 patients with mild, moderate or severe lissencephaly that reflect disease severity in the degree of alterations of cytoarchitecture and neurogenesis. ScRNAseq data point toward a severity related dysregulation of progenitor cell homeostasis. Furthermore, we show that severity dependent alteration in microtubule stabilization is critical for the development of the phenotype. In addition, we found alterations in niche-dependent WNT-signaling mainly in severe patient-derived organoids. Thus, our data identify for the first time a clear association between the clinical severity grade of the patients and the molecular phenotype in the organoid model, suggest linked disease-mechanisms and show the sensitivity of organoid-based systems to capture different disease severities in vitro .