Objective: To investigate the phenotypic and genotypic spectrum of GNB1 (guanine nucleotide-binding protein, beta 1) mutations and to functionally evaluate their pathogenicity.

Background: Global developmental delay (GDD) is a severe, clinically and genetically highly heterogeneous childhood-onset disorder which is often accompanied by intellectual disability, seizures and other features. In cases in which genetic causes have been identified, de novo mutations in neuronally expressed genes are a common scenario. De novo mutations in the GNB1 gene, encoding the Gβ1 subunit of heterotrimeric G proteins, have recently been identified as a novel genetic cause of GDD. Of note, several of the patients also had dystonic features including a patient with severe generalized dystonia.

Methods: We searched the in-house database of 4,361 exome datasets at Centogene AG for rare variants in GNB1. Missense changes were functionally tested for their pathogenicity by assaying the impact on complex formation with Gγ and resultant mutant Gβγ with Gα. Signaling properties of G protein complexes carrying mutant Gβ1 subunits were further analyzed for their ability to couple to dopamine D1R receptors by real-time Bioluminescence Resonance Energy Transfer (BRET) assays.

Results: The pediatric patients presented with intellectual disability, seizures, nystagmus, muscular hyptonia, ophthalmoplegia, abnormal myelination, craniosynostosis, cerebellar hypoplasia, ataxia, chorea, and dystonia. First symptoms occurred at a mean age of 5.3±2.8 (range: 1-12 years). We identified 14 different novel variants (2 splice site, 2 frameshift, and 10 missense changes) in GNB1 in 16 patients. One mutation (R96L) was recurrently found in three ethnically diverse families with an autosomal dominant mode of inheritance. Ten variants occurred de novo in the patients. BRET studies revealed altered functionality of the missense mutations R52G, G64V, A92T, P94S, P96L, A106T, and D118G but not for L30F, H91R, and K337Q.

Conclusions: We demonstrate a pathogenic role of de novo and autosomal dominant mutations in GNB1 as a likely cause of GDD in combination with and movement disorders and provide insights how perturbation in heterotrimeric G protein function contributes to the disorder.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterization-of-gnb1-mutations-as-a-cause-of-global-developmental-delay-in-combination-with-dystonia-ataxia-or-chorea-in-children/