title: 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.679G>C; 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.
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chatron
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Labalme
authors.affiliation: Department of Pediatric Neurology, Lyon University Hospitals, Lyon, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.affiliation: Department of Pediatric Neurology, Lyon University Hospitals, Lyon, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Carneiro
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Edery
authors.affiliation: Department of Pediatric Neurology, Lyon University Hospitals, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.affiliation: Department of Genetics, Lyon University Hospitals, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
mesh_terms: D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D035781:Siblings; D013577:Syndrome
chemical_list: C485668:GRIN1 protein, human; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate