Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy

Abstract

We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1. Massive parallel sequencing was performed using a gene panel including 450 genes related to intellectual disability and autism spectrum disorders. We found a homozygous missense variation of GRIN1 (c.679G4C; p.(Asp227His)) in the two affected sibs, which was inherited from both unaffected heterozygous parents. Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders. The p.(Asp227His) variant is located in the same aminoterminal protein domain as the recently published p.(Arg217Trp), which was found at the homozygous state in two patients with a similar phenotype of severe intellectual disability and autistic features but without epilepsy. In silico predictions were consistent with a deleterious effect. The present findings further expand the clinical spectrum of GRIN1 variants and support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance. European Journal of Human Genetics (2017) 25, 376-380; doi:10.1038/ejhg.2016.163; published online 4 January 2017 INTRODUCTION GRIN1 (MIM *138249) encodes the GluN1 subunit of N-methyl-Daspartate receptors, members of the glutamate receptor channel superfamily, which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits have a key role in the plasticity of synapses, which underlies memory and learning. 1 De novo heterozygous variants of GRIN1 were first identified by targeted Sanger sequencing in two patients with intellectual disability (ID) with or without epilepsy (MIM #614254). 2 Recent advances in nextgeneration sequencing have shown that GRIN1 de novo heterozygous variants represent a recurrent cause of epileptic encephalopathy with early onset. 3,4 A recent paper provided a better delineation of the GRIN1 phenotypic spectrum that includes severe ID with absent speech, muscular hypotonia, hyperkinetic movements, oculogyric crises, hand stereotypies, cortical blindness, and epilepsy. 5 This article also reported for the first time two homozygous GRIN1 variants in families with severe neurodevelopmental phenotypes.In the present paper we report a second family including two affected sibs with a homozygous missense variant, thus expanding the phenotype-genotype correlations related to GRIN1 variants.

Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models

“…Subunits confer different functional properties to the receptor. 3 Rare variant in ASD siblings [ 76 ] Thermo 54.1 Cat# 02-0500 Santa Cruz polyclonal C20 Cat# sc-1467 GRIN2A NMDAR2A 4 Genetic association [ 77 ] Neuromab N327/95 Cat#75-288 Biolegend N327A/38 Cat# 832401 GRIN2B NMDAR2B 1 Multiple rare variants identified in ASD patients. [ 4 , 78 , 79 ] Biolegend N59/20 Cat# 832501 Biolegend N59/36 Cat# 818701 GRIA1 GluR1 AMPA-type glutamate receptor subunits.…”

Transcriptomics of Gabra4 knockout mice reveals common NMDAR pathways underlying autism, memory, and epilepsy

“…Some of these genes are well known to be involved in autism. For example, mutations in Grin1 [50], Myh10 [51,52], Mapk1 [53], and Atp1a3 [54] were found in autism patients or mice. The expression change of these genes may perturb the subnetwork of autism, leading to autistic-like phenotypes of the knockout mice.…”

Modeling and treatingGRIN2Adevelopmental and epileptic encephalopathy in mice

“…4c inset), indicating that hearing per se was not impaired but the reaction to stimulus is altered. Because NMDAR mutations are associated with autism spectrum disorder (ASD, (Hacohen et al, 2016;Grea et al, 2017;Rossi et al, 2017) and repetitive behavior in mice (Lee et al, 2015;Kim et al, 2019), we evaluated additional ASD-relevant behaviors using established criteria in rodents. Although S644G/+ mice showed no impairments in the same-sex reciprocal social interaction test (Supplementary Fig.…”