Abstract
ObjectiveDefects 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‐protein‐coupled 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.MethodsExome 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.ResultsWe 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 childhood.ConclusionDetailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.
Highlights
Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathies (DEEs) by impairing central nervous system (CNS) neurotransmission.[1,2] One such important group of receptors is the glutamate receptors
Glutamate is an excitatory neurotransmitter that has been extensively studied in epilepsy and that acts through two main receptor groups: ionotropic glutamate receptors and metabotropic glutamate receptors.[3]
Rare monoallelic and biallelic single nucleotide variants (SNVs) and copy number variants (CNVs) in genes encoding postsynaptic ionotropic glutamate receptors (iGluRs) subunits such as GRIN1, GRIN2A, GRIN2B, and GRIN2D encoding the NR1, NR2A, NR2B, and NR2D subunits of N-methyl-D-aspartate receptor (NMDAR), respectively, GRIA2-4 encoding the GluR2-4 subunits of amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPAR), and GRIK2 encoding the GluR6 subunit of kainate receptor (KAR) have been shown to cause a wide range of neurodevelopmental disorders (NDDs) and DEEs.[4,5,6,7,8,9,10,11]
Summary
Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathies (DEEs) by impairing central nervous system (CNS) neurotransmission.[1,2] One such important group of receptors is the glutamate receptors. Glutamate is an excitatory neurotransmitter that has been extensively studied in epilepsy and that acts through two main receptor groups: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs).[3] The iGluRs include N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPAR), and kainate receptor (KAR). Rare monoallelic and biallelic single nucleotide variants (SNVs) and copy number variants (CNVs) in genes encoding postsynaptic iGluRs subunits such as GRIN1, GRIN2A, GRIN2B, and GRIN2D encoding the NR1, NR2A, NR2B, and NR2D subunits of NMDAR, respectively, GRIA2-4 encoding the GluR2-4 subunits of AMPAR, and GRIK2 encoding the GluR6 subunit of KAR have been shown to cause a wide range of neurodevelopmental disorders (NDDs) and DEEs.[4,5,6,7,8,9,10,11]. Biallelic rare variants in GRM1 have been shown to cause cerebellar ataxia.[15]
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