Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Abstract

Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-proteincoupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T: p.Arg659Ter). Developmental delay, neonatal-or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late 610 childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes

“…All affected children were reported to exhibit global developmental delay, intellectual disability, epilepsy, and microcephaly. The phenotype of the individuals presented here matches the other published cases ( 9 , 11 ). Their seizures have responded well to antiepileptic drugs, which is similar to patients with the same variant, but contrasts with patients with other variants who exhibited drug-resistant epilepsy ( 11 ).…”

“…The phenotype of the individuals presented here matches the other published cases ( 9 , 11 ). Their seizures have responded well to antiepileptic drugs, which is similar to patients with the same variant, but contrasts with patients with other variants who exhibited drug-resistant epilepsy ( 11 ). We also noted transient stereotypic movements in these patients in the form of head nodding and hand clasping.…”

“…Here we present clinical findings in parallel with the functional characterization of a disease-associated mutation affecting the mGlu 7 receptor. Recently, biallelic mutations in GRM7 were reported in 11 patients from 6 unrelated families, 2 of whom have the same mutation described here ( 11 ). All affected children were reported to exhibit global developmental delay, intellectual disability, epilepsy, and microcephaly.…”

“…In recent years, whole exome sequencing (WES) studies have identified rare deletions and variants in GRM7 , the human gene encoding mGlu 7 , in patients with neurodevelopmental disorders. Heterozygous deletions and point mutations have been reported in patients with autism spectrum disorder (ASD) ( 5 – 7 ) and attention deficit hyperactivity disorder ( 8 ), whereas homozygous point mutations have been found in rare cases of severe developmental delay, microcephaly, and epilepsy ( 9 – 11 ). However, the consequences of these mutations on mGlu 7 receptor function and a causal role in disease pathogenesis have not yet been determined.…”

“…Here, we present new clinical cases of 2 sisters with severe developmental delay and epilepsy confirmed to be homozygous for a GRM7 variant c.461T>C p.Ile154Thr (mGlu 7 -I154T). This variant was first identified by WES in 2 brothers in 2016, and detailed clinical information was recently published ( 9 , 11 ). Functional studies of the mGlu 7 -I154T mutant protein in HEK293A cells and knockin mice reveal that this single amino acid change is sufficient to substantially reduce mGlu 7 protein levels and produce a range of neurological phenotypes in mice, thus providing further support for GRM7 as a causative gene in neurodevelopmental disorders.…”