Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia

doi:10.1038/s10038-020-00846-1

Case Reports

. 2021 Mar;66(3):339-343.

doi: 10.1038/s10038-020-00846-1. Epub 2020 Sep 18.

Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia

Anna Alkelai¹, Shahar Shohat², Lior Greenbaum^{3

4

5}, Tanya Schechter⁶, Benjamin Draiman⁶, Eti Chitrit-Raveh⁶, Shlomit Rienstein³, Neha Dagaonkar⁷, Daniel Hughes⁷, Vimla S Aggarwal⁷, Erin L Heinzen^{7

8}, Sagiv Shifman², David B Goldstein⁷, Yoav Kohn^{6

9}

Affiliations

¹ Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA. aa3857@cumc.columbia.edu.
² Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
³ The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
⁴ The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel.
⁵ Sackler Faculty of Medicine, Tal Aviv University, Tel Aviv, Israel.
⁶ Department of Child and Adolescent Psychiatry, Jerusalem Mental Health Center, Eitanim Psychiatric Hospital, Jerusalem, Israel.
⁷ Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.
⁸ Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
⁹ Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.

PMID: 32948840
DOI: 10.1038/s10038-020-00846-1

Case Reports

Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia

Anna Alkelai et al. J Hum Genet. 2021 Mar.

. 2021 Mar;66(3):339-343.

doi: 10.1038/s10038-020-00846-1. Epub 2020 Sep 18.

Authors

Affiliations

¹ Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA. aa3857@cumc.columbia.edu.
² Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
³ The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
⁴ The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel.
⁵ Sackler Faculty of Medicine, Tal Aviv University, Tel Aviv, Israel.
⁶ Department of Child and Adolescent Psychiatry, Jerusalem Mental Health Center, Eitanim Psychiatric Hospital, Jerusalem, Israel.
⁷ Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.
⁸ Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
⁹ Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.

PMID: 32948840
DOI: 10.1038/s10038-020-00846-1

Abstract

Childhood-onset schizophrenia (COS) is a rare form of schizophrenia with an onset before 13 years of age. There is rising evidence that genetic factors play a major role in COS etiology, yet, only a few single gene mutations have been discovered. Here we present a diagnostic whole-exome sequencing (WES) in an Israeli Jewish female with COS and additional neuropsychiatric conditions such as obsessive-compulsive disorder (OCD), anxiety, and aggressive behavior. Variant analysis revealed a de novo novel stop gained variant in GRIA2 gene (NM_000826.4: c.1522 G > T (p.Glu508Ter)). GRIA2 encodes for a subunit of the AMPA sensitive glutamate receptor (GluA2) that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. GluA2 subunit mutations are known to cause variable neurodevelopmental phenotypes including intellectual disability, autism spectrum disorder, epilepsy, and OCD. Our findings support the potential diagnostic role of WES in COS, identify GRIA2 as possible cause to a broad psychiatric phenotype that includes COS as a major manifestation and expand the previously reported GRIA2 loss of function phenotypes.

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References

1. McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-an overview. JAMA Psychiatry. 2020;77:201–10. - DOI
1. Fernandez A, Drozd MM, Thummler S, Dor E, Capovilla M, Askenazy F, et al. Childhood-onset schizophrenia: a systematic overview of its genetic heterogeneity from classical studies to the genomic era. Front Genet. 2019;10:1137. - DOI
1. Fernandez A, Dor E, Maurin T, Laure G, Menard ML, Drozd M, et al. Exploration and characterisation of the phenotypic and genetic profiles of patients with early onset schizophrenia associated with autism spectrum disorder and their first-degree relatives: a French multicentre case series study protocol (GenAuDiss). BMJ Open. 2018;8:e023330. - PubMed - PMC
1. Ambalavanan A, Chaumette B, Zhou S, Xie P, He Q, Spiegelman D, et al. Exome sequencing of sporadic childhood-onset schizophrenia suggests the contribution of X-linked genes in males. Am J Med Genet B Neuropsychiatr Genet. 2019;180:335–40. - DOI
1. Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, et al. A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol Psychiatry. 2011;16:238–9. - DOI

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[1] McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-an overview. JAMA Psychiatry. 2020;77:201–10. - DOI

[2] McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-an overview. JAMA Psychiatry. 2020;77:201–10. - DOI

[3] Fernandez A, Drozd MM, Thummler S, Dor E, Capovilla M, Askenazy F, et al. Childhood-onset schizophrenia: a systematic overview of its genetic heterogeneity from classical studies to the genomic era. Front Genet. 2019;10:1137. - DOI

[4] Fernandez A, Drozd MM, Thummler S, Dor E, Capovilla M, Askenazy F, et al. Childhood-onset schizophrenia: a systematic overview of its genetic heterogeneity from classical studies to the genomic era. Front Genet. 2019;10:1137. - DOI

[5] Fernandez A, Dor E, Maurin T, Laure G, Menard ML, Drozd M, et al. Exploration and characterisation of the phenotypic and genetic profiles of patients with early onset schizophrenia associated with autism spectrum disorder and their first-degree relatives: a French multicentre case series study protocol (GenAuDiss). BMJ Open. 2018;8:e023330. - PubMed - PMC

[6] Fernandez A, Dor E, Maurin T, Laure G, Menard ML, Drozd M, et al. Exploration and characterisation of the phenotypic and genetic profiles of patients with early onset schizophrenia associated with autism spectrum disorder and their first-degree relatives: a French multicentre case series study protocol (GenAuDiss). BMJ Open. 2018;8:e023330. - PubMed - PMC

[7] Ambalavanan A, Chaumette B, Zhou S, Xie P, He Q, Spiegelman D, et al. Exome sequencing of sporadic childhood-onset schizophrenia suggests the contribution of X-linked genes in males. Am J Med Genet B Neuropsychiatr Genet. 2019;180:335–40. - DOI

[8] Ambalavanan A, Chaumette B, Zhou S, Xie P, He Q, Spiegelman D, et al. Exome sequencing of sporadic childhood-onset schizophrenia suggests the contribution of X-linked genes in males. Am J Med Genet B Neuropsychiatr Genet. 2019;180:335–40. - DOI

[9] Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, et al. A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol Psychiatry. 2011;16:238–9. - DOI

[10] Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, et al. A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol Psychiatry. 2011;16:238–9. - DOI

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Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia

Affiliations

Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia

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Abstract

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