# Atypical GNAO1 variants in severe childhood speech disorders: clinical, genetic, and molecular insights

## TL;DR

This study explores rare GNAO1 gene variants in children with severe speech disorders and intellectual disability, revealing new molecular mechanisms and potential zinc-based treatments.

## Contribution

The study identifies novel GNAO1 variants linked to speech disorders and ID, expanding the known clinical and molecular spectrum of GNAO1-related conditions.

## Key findings

- Three atypical GNAO1 variants show impaired GTP binding, altered RGS19 association, and increased Ric8A interaction.
- All variants localize to the plasma membrane but differ in receptor coupling and respond positively to Zn2+.
- Severe speech disorders and ID can occur without seizures or movement disorders in GNAO1-related cases.

## Abstract

The etiology of severe childhood speech disorders, including childhood apraxia of speech (CAS), is currently understood as genetically heterogeneous, with over 40 distinct monogenic conditions reported to date. Among them, the p.Thr327Arg variant in GNAO1, encoding the major neuronal G protein Gαo, was identified in one patient diagnosed with CAS and intellectual disability (ID). This presentation is exceptionally rare, as GNAO1 mutations are commonly associated with epilepsy, hyperkinetic movement disorders, and global developmental delay, often accompanied by ID.

Here, we describe the clinical course of two patients with de novo heterozygous GNAO1 variants—p.Leu39_Gly40insVal and p.Thr327Lys—who exhibit severe speech disorder and ID as prominent symptoms. We also analyzed the biochemical and cellular properties of the mutant Gαo proteins alongside the previously reported p.Thr327Arg variant.

Molecular investigation of these three atypical Gαo mutants revealed aberrant GTP binding and hydrolysis, impaired association with RGS19, and a strong neomorphic gain of Ric8A interaction. Yet, all variants show normal plasma membrane localization despite poor Gβγ association, with p.Leu39_Gly40insVal exhibiting weak coupling to G protein-coupled receptors and p.Thr327Arg/Lys displaying near-normal coupling. Importantly, all three Gαo variants respond to Zn2+, supporting the potential therapeutic use of zinc supplementation for the patients.

These rare findings are based on a limited number of cases and require confirmation in additional patients to establish firmer genotype–phenotype correlations for GNAO1-related severe speech disorders.

Our results broaden the clinical and mechanistic spectrum of GNAO1-related disorders, showing that severe speech disorders and ID can occur as defining features even in the absence of seizures or movement disorders. These findings highlight the importance of including GNAO1 in genetic testing for children with severe speech disorders.

The online version contains supplementary material available at 10.1186/s13229-025-00696-8.