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

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. 1.

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

    Article  Google Scholar 

  2. 2.

    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.

    Article  CAS  Google Scholar 

  3. 3.

    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  PubMed Central  Google Scholar 

  4. 4.

    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.

    Article  CAS  Google Scholar 

  5. 5.

    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.

    Article  CAS  Google Scholar 

  6. 6.

    Ambalavanan A, Girard SL, Ahn K, Zhou S, Dionne-Laporte A, Spiegelman D, et al. De novo variants in sporadic cases of childhood onset schizophrenia. Eur J Hum Genet. 2016;24:944–8.

    Article  Google Scholar 

  7. 7.

    Sheikh TI, Harripaul R, Ayub M, Vincent JB. MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro. Hum Mutat. 2018;39:717–28.

    Article  CAS  Google Scholar 

  8. 8.

    Smedemark-Margulies N, Brownstein CA, Vargas S, Tembulkar SK, Towne MC, Shi J, et al. A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia. Cold Spring Harb Mol Case Stud. 2016;2:a001008.

    Article  CAS  Google Scholar 

  9. 9.

    Chaumette B, Ferrafiat V, Ambalavanan A, Goldenberg A, Dionne-Laporte A, Spiegelman D, et al. Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia. Mol Psychiatry. 2020;25:821–30.

    Article  CAS  Google Scholar 

  10. 10.

    Kirov G, Rees E, Walters JT, Escott-Price V, Georgieva L, Richards AL, et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 2014;75:378–85.

    Article  CAS  Google Scholar 

  11. 11.

    Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu YF, McSweeney KM, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med. 2015;17:774–81.

    Article  CAS  Google Scholar 

  12. 12.

    Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49:353–61.

    Article  CAS  Google Scholar 

  13. 13.

    Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9:e1003709.

    Article  CAS  Google Scholar 

  14. 14.

    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536:285–91.

    Article  CAS  Google Scholar 

  15. 15.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  16. 16.

    Henley JM, Wilkinson KA. AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging. Dialogues Clin Neurosci. 2013;15:11–27.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Salpietro V, Dixon CL, Guo H, Bello OD, Vandrovcova J, Efthymiou S, et al. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. Nat Commun. 2019;10:3094.

    Article  CAS  Google Scholar 

  18. 18.

    Chang PK, Verbich D, McKinney RA. AMPA receptors as drug targets in neurological disease-advantages, caveats, and future outlook. Eur J Neurosci. 2012;35:1908–16.

    Article  Google Scholar 

  19. 19.

    Bozorgmehr A, Ghadirivasfi M, Shahsavand Ananloo E. Obsessive-compulsive disorder, which genes? Which functions? Which pathways? An integrated holistic view regarding OCD and its complex genetic etiology. J Neurogenet. 2017;31:153–60.

    Article  CAS  Google Scholar 

  20. 20.

    Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008;82:696–711.

    Article  CAS  Google Scholar 

  21. 21.

    Uno Y, Coyle JT. Glutamate hypothesis in schizophrenia. Psychiatry Clin Neurosci. 2019;73:204–15.

    Article  Google Scholar 

  22. 22.

    Rubio MD, Drummond JB, Meador-Woodruff JH. Glutamate receptor abnormalities in schizophrenia: implications for innovative treatments. Biomol Ther. 2012;20:1–18.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by a grant from the National Institute for Psychobiology in Israel to YK and SS. We thank the patient and her parents for participation in the study.

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Correspondence to Anna Alkelai.

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DBG reports equity holdings in precision medicine companies (Q State – Pairnomix, Praxis Therapeutics, Apostle Inc.) and consultancy payments from Gilead Sciences, AstraZeneca, and GoldFinch Bio.

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Alkelai, A., Shohat, S., Greenbaum, L. et al. Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia. J Hum Genet (2020). https://doi.org/10.1038/s10038-020-00846-1

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