NEW YORK (GenomeWeb) - A team from Iceland, Finland, and Germany have found evidence that links some forms of psychosis to mutations that lop off the end of the RNA-binding motif protein 12-coding gene RBM12.
As they reported online today in Nature Genetics, the researchers used genotyping and imputation-based long-range phasing to search for risky variants in a family from Iceland that included six individuals with of schizophrenia and two family members apiece with schizoaffective disorder or psychotic bipolar disorder. They also profiled seven psychosis-affected family members by whole-genome sequencing.
With genetic data from that family — and from a psychosis-affected family from Finland — the team narrowed in on a rare, psychosis-related truncation mutation in RBM12. Although that mutation did segregate with psychosis, it did not appear to be fully penetrant. Instead, the group reported that some individuals carrying the mutation did share non-psychosis-related psychiatric and neuropsychological features with their affected relatives.
"In addition to identifying RBM12 … the work reported here provides a template for future familial studies of psychosis, suggesting that the mutations involved are likely to be recent, may be incompletely penetrant for psychosis, but lead to related phenotypes in carriers unaffected by psychosis, and are likely to act in concert with other sequence variants," corresponding author Kari Stefansson, with Decode/Amgen and the University of Iceland, and his colleagues wrote.
Based on array-based genotypes, long-range phasing, and/or genome sequence data for the 10 individuals with psychosis from the first family, the researchers narrowed in on a shared nonsense mutation in the last coding exon of RBM12 that was verified with Sanger sequencing.
The alteration did not turn up in the Genome Aggregation Database (gnomAD), they reported, and was identified in fewer than two dozen other Icelanders, all descended from the family in question.
Along with experiments done to gauge expression of the RBM12 in lymphoblast cell lines from several individuals who did or did not carry mutated versions of the gene, the team scoured sequence databases for other suspicious looking changes in RBM12, narrowing in on another mutation in the gene in an individual from Finland who had been diagnosed with schizophrenia.
That individual also carried a chromosome 22 deletion already associated with psychosis, the authors noted. But the same deletion was not present in four siblings with psychosis who shared RBM12 with the first Finnish family member. Conversely, unaffected siblings did carry the chromosome 22 deletion. The RBM12 mutation did not turn up in the unaffected Finnish family members, though findings from the Icelandic family indicated that mutations in that gene are not fully penetrant.
"Today's capacity for whole-exome and whole-genome sequencing makes it likely that additional high-penetrance, familial mutations will be discovered," Stefansson and co-authors wrote.