GABAB receptors are obligatory heterodimers responsible for prolonged neuronal inhibition in the central nervous system. The two receptor subunits are encoded by GABBR1 and GABBR2. Variants in GABBR2 have been associated with a Rett-like phenotype (MIM: 617903), epileptic encephalopathy (MIM: 617904), and milder forms of developmental delay with absence epilepsy. To date, however, no phenotypes associated with pathogenic variants of GABBR1 have been established. Through GeneMatcher, we have ascertained four individuals who each have a monoallelic GABBR1 de novo non-synonymous variant; these individuals exhibit motor and/or language delay, ranging from mild to severe, and in one case, epilepsy. Further phenotypic features include varying degrees of intellectual disability, learning difficulties, autism, ADHD, ODD, sleep disorders, and muscular hypotonia. We functionally characterized the four de novo GABBR1 variants, p.Glu368Asp, p.Ala397Val, p.Ala535Thr, and p.Gly673Asp, in transfected HEK293 cells. GABA fails to efficiently activate the variant receptors, most likely leading to an increase in the excitation/inhibition balance in the central nervous system. Variant p.Gly673Asp in transmembrane domain 3 (TMD3) renders the receptor completely inactive, consistent with failure of the receptor to reach the cell surface. p.Glu368Asp is located near the orthosteric binding site and reduces GABA potency and efficacy at the receptor. GABA exhibits normal potency but decreased efficacy at the p.Ala397Val and p.Ala535Thr variants. Functional characterization of GABBR1-related variants provides a rationale for understanding the severity of disease phenotypes and points to possible therapeutic strategies.

Department of Biomedicine Pharmazentrum University of Basel Klingelbergstrasse 50 70 4056 Basel Switzerland

Department of Pediatrics 1st Faculty of Medicine Charles University and University Thomayer Hospital Prague Prague Czech Republic

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Division of Neuropaediatrics Hospital for Children and Adolescents University Hospital Leipzig Leipzig Germany

Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany

Medigenome Swiss Institute of Genomic Medicine 1207 Geneva Switzerland

Washington University in St Louis St Louis MO USA

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