Supplementary Material for: A Novel Intracellular Domain Missense Variant in GRM7 Associated with Early-Onset Neurodevelopmental Encephalopathy

Introduction: Biallelic pathogenic variants in the GRM7 gene, which encodes the metabotropic glutamate receptor 7 (mGlu7), have been associated with early-onset neurodevelopmental disorders characterised 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.
Case presentation: 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 absent from population databases and affects a highly conserved residue. In silico prediction tools support 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 alongside preserved myelination.
Conclusion: This case expands the phenotypic and genotypic spectrum of GRM7-associated neurodevelopmental disorders, highlighting the potential significance of intracellular domain variants, which are underrepresented in the 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 signalling and clinical outcome.