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


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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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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