Overview and expansion of CEP85L-associated lissencephaly

Defective neuronal migration causes lissencephaly (LIS), a neurodevelopmental disorder (NDD) with a smooth cerebral surface and abnormal cortical thickness. Variants in CEP85L are linked to posterior predominant LIS, but the phenotype and genotype are unclear. Three new unrelated cases of CEP85L-associated LIS are presented, including the first prenatal diagnosis and a mosaic variant. Clinical, neuroimaging, and genetic analyses were recorded. Data from 29 previously reported individuals was used in a comprehensive literature review. Human phenotype ontology (HPO) terms were used to annotate phenotypic features, and American College of Medical Genetics and Genomics (ACMG) guidelines were used to evaluate variants. All postnatal individuals had variable NDD. Global developmental delay was observed in 71 % (22/31), speech or motor delay in 54 % (11/31 and 6/31, respectively), and intellectual disability in 74 % (23/31) of cases. Focused and generalized-onset seizures occurred in 90 % (28/31). Brain magnetic resonance imaging (MRI) revealed predominantly posteriorly predominant LIS in all evaluated individuals, with 55 % (17/31) of cases also exhibiting subcortical band heterotopia (SBH). A total of 18 different CEP85L variants were identified among all individuals, all clustering in a highly conserved N-terminal region between amino acids 1 and 103. These included 10 missense mutations, five splice-site alterations, two start-loss variants, and one stop variant. Nine de novo variants, 10 mother-father variants, and 13 variants with unknown inheritance. Genotype-phenotype correlations in CEP85L-associated LIS show that stronger splice and germline variants often cause more severe symptoms than mosaic variants. To reduce confusion caused by alternative CEP85L transcripts, we recommend NM_001042475 for variant interpretation. These findings improve this disorder's genetic diagnostics and counseling framework.