Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Area of Science:

• Neurogenetics
• Molecular Neurology
• Epileptology

Background:

• Defects in ion channels and neurotransmitter receptors are linked to developmental and epileptic encephalopathy (DEE).
• Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is crucial for synaptic transmission.
• GRM7 was previously suggested as a candidate gene for neurodevelopmental disorders (NDDs).

Purpose of the Study:

• To investigate the role of GRM7 biallelic variants in DEE.
• To characterize the clinical, neurological, and electrophysiological phenotype associated with GRM7 variants.
• To analyze molecular data from affected individuals.

Main Methods:

• Exome sequencing and family-based rare variant analysis in 220 consanguineous families with NDDs.
• Identification of three additional families through literature and collaboration.
• Clinical and molecular data comparison across 11 affected individuals from six families.

Main Results:

• Three novel deleterious GRM7 variants identified: two missense and one stop-gain.
• Universal features included developmental delay, epilepsy, and microcephaly.
• Cerebral atrophy, hypomyelination, and hypothalamic-pituitary-axis dysfunction were observed; five individuals died in childhood.

Conclusions:

• Rare biallelic GRM7 pathogenic variants are a cause of DEEs.
• GRM7 variants are associated with microcephaly, hypomyelination, and cerebral atrophy.
• This study expands the understanding of GRM7-related neurodevelopmental disorders.