Recent genetic findings suggest shared genetic risk between autism, epilepsy and schizophrenia. A sodium channel subunit gene, SCN2A, exhibits de novo stop-codon mutations in individuals with autism and a stop-codon mutation in an individual with a seizure disorder. Our recent exome-sequencing study of schizophrenia cases identified a de novo splicesite mutation at SCN2A and further mutations may exist.

To examine a role for rare, protein damaging mutations at SCN2A in the aetiology of schizophrenia.

We aim to show an excess of coding sequence mutations in schizophrenia cases when compared to controls.

Mutation screening of the coding sequence of SCN2A in 993 Caucasian individuals with DSM-IV schizophrenia. We employed High-Resolution Melt Analysis(LightScanner™), followed by dye- terminator sequencing to confirm allele carriers. We compared our results to an exome-sequencing dataset of 4300 Caucasian individuals (NHLBI Exome Sequencing Project).

34 variants were identified; 15 intronic, 13 synonymous and 7 non-synonymous. One of the non-synonymous variants introduces a stop codon at amino acid 169 (169 E>X). No stop-codon variants were identified in the control dataset. Burden analysis did not show an excess of protein damaging changes in the UK dataset when compared to controls.

A total of 4 stop-codon mutations have been identified at SCN2A; all in individuals with a neuropsychiatric disorder. Our data do not suggest a general role for protein coding mutations at SCN2A in the pathogenesis of schizophrenia; however there may be a role for very damaging alleles at SCN2A in several neuropsychiatric disorders.