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Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation
Open accessAbstract
OBJECTIVES: There is a growing body of evidence suggesting a shared genetic susceptibility between many neuropsychiatric disorders, including schizophrenia, autism, intellectual disability (ID) and epilepsy. The sodium channel, voltage-gated type II α subunit gene SCN2A has been shown to exhibit loss-of-function (LoF) mutations in individuals with seizure disorders, ID, autism and schizophrenia. The role of LoF mutations in schizophrenia is still uncertain with only one such mutation identified to date. METHODS: To seek additional evidence for a role for LoF mutations at SCN2A in schizophrenia we performed mutation screening of the entire coding sequence in 980 schizophrenia cases. Given an absence of LoF mutations in a public exome cohort (ESP6500, N=6503), we did not additionally sequence controls. RESULTS: We identified a novel, nonsense (i.e. stop codon) mutation in one case (E169X) that is absent in 4300 European-American and 2203 African-American individuals from the NHLBI Exome Sequencing Project. This is the second LoF allele identified in a schizophrenia case to date. We also show a novel, missense variant, V1282F, that occurs in two cases and is absent in the control dataset. CONCLUSION: We argue that very rare, LoF mutations at SCN2A act in a moderately penetrant manner to increase the risk of developing several neuropsychiatric disorders including seizure disorders, ID, autism and schizophrenia.
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“While most children with SCN2A variants fit into one of these three categories, there are some exceptions, including epileptic encephalopathy with choreoathetoid movements [26,27], benign infantile seizures with late-onset episodic ataxia [28–31], childhood-onset epileptic encephalopathy [32], and schizophrenia [33,34].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [34]
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“Similarly, rare loss-of-function mutations have been reported in the SCN2A gene, a hub gene of the INH-M11 module.44”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [44]
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“Similarly, rare loss-of-function mutations have been reported in the SCN2A gene, a hub gene of the INH-M11 module.44”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [44]
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“While most children with SCN2A variants fit into one of these three categories, there are some exceptions, including epileptic encephalopathy with choreoathetoid movements [26,27], BISs with late-onset episodic ataxia [28–31], childhood-onset epileptic encephalopathy [32], and schizophrenia [33,34].”
BackgroundIon Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies
Oyrer, J., Maljevic, S., Scheffer, I. E., Berkovic, S. F., Petrou, S., & Reid, C. A. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014456 · Cited by 315
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Metadata
- Authors
- Carroll, L. S., Woolf, R., Ibrahim, Y., Williams, H. J., Dwyer, S., Walters, J., Kirov, G., O’Donovan, M. C., & Owen, M. J.
- Affiliations
- Cardiff University (GB)
- Corresponding author
- Carroll, Liam S.
- ORCID
- Venue
- Psychiatric Genetics
- Published
- 2016-04
- Volume
- 26
- Issue
- 2
- Pages
- 60-65
- ISSN
- 0955-8829 (ISSN-L)
- PMC
- PMC4756433
- OpenAlex
- W2177779297
- Cited by
- 54
- References
- 53
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 9 · 2018: 6 · 2017: 6 · 2016: 1
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- Wellcome Trust
- Research Councils UK
- Medical Research Council (MR/L010305/1)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- SCN2A, schizophrenia, loss-of-function mutations, nonsense mutation, missense mutations, intellectual disability, autism spectrum disorder, epilepsy, shared genetic risk
- MeSH terms
- DNA Mutational Analysis, Female, United Kingdom, Humans, Male, Schizophrenia, Genetic Predisposition to Disease, Mutation, Missense, NAV1.2 Voltage-Gated Sodium Channel
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