A Novel Intracellular Domain Missense Variant in GRM7 Associated with Early-Onset Neurodevelopmental Encephalopathy

Biallelic pathogenic variants in the GRM7 gene, which encodes the metabotropic glutamate receptor 7 (mGlu7), have been associated with early-onset neurodevelopmental disorders characterized by epilepsy, developmental delay, and white matter abnormalities. However, reported cases predominantly involve variants affecting the extracellular or transmembrane domains, and the full phenotypic spectrum remains unclear.

We present the case of a male patient exhibiting early-onset focal epilepsy, global developmental delay, and neuroimaging evidence of corpus callosum thinning alongside normal myelination. Clinical exome sequencing identified a novel homozygous missense variant in the intracellular C-terminal domain of GRM7 (c.2528C>T; p.(Pro843Leu)). This variant is present at extremely low frequency in population databases and has not been reported in the homozygous state. It also affects a highly conserved residue. In silico prediction tools support the assessment of its pathogenicity. While the patient's clinical features partially overlap with those reported in other GRM7-associated cases, they are notable for the absence of primary microcephaly and the presence of isolated motor delay, along with preserved myelination.

This report adds further clinical and genetic evidence to the growing literature on GRM7-associated neurodevelopmental disorders and highlights the potential relevance of intracellular domain variants, which are underrepresented in the current literature. GRM7 should be included in diagnostic gene panels for infantile-onset epilepsy and developmental delay, particularly in populations with high consanguinity rates. Further functional studies are needed to clarify the impact of intracellular GRM7 variants on receptor signaling and clinical outcome.