Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated.Results: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. Conclusion: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying

The broad application of next-generation sequencing in genetic diagnostics opens up vast possibilities for personalized treatment of patients with genetic disorders including monogenic epilepsies. To translate genetic findings into personalized medicine, mechanistic studies of the individual pathogenic variants and drug screening in patient-specific in vitro models are very crucial. Recently, human induced pluripotent stem cell (hiPSC) technologies have made it possible to generate patient-specific pluripotent cells, which can be directed to differentiate into any given cell type. These hiPSCs are ideal for generating neurons to investigate specific neurological/ neurodevelopmental disorders. While two-dimensional single-cell models of hiPSC-derived neurons provide reliable investigation of synaptic transmission and plasticity, cerebral organoids are superior in regard to functional characterization and the study of cell-cell interactions in three-dimensional structures. In this review, we focus on monogenic epilepsies and discuss the application of hiPSC models in personalized drug treatment based on the patient's specific genetic variants.