Truncating mutations in RBM12 are associated with psychosis

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Limited understanding of genetic factors contributing to psychosis risk.
• Previous research identified a few highly penetrant mutations associated with psychosis.

Purpose of the Study:

• To investigate genetic causes of psychosis in an Icelandic kindred using whole-genome sequencing.
• To identify novel genes associated with schizophrenia, schizoaffective disorder, and psychotic bipolar disorder.

Main Methods:

• Whole-genome sequencing and long-range phasing in an Icelandic family.
• Replication study in a Finnish family with a second RBM12 mutation.
• Analysis of unaffected RBM12 mutation carriers for psychiatric and neuropsychological profiles.

Main Results:

• A nonsense mutation in RBM12 (c.2377G>T) was found in all affected individuals in the Icelandic kindred (P = 2.2 × 10^-4).
• A second truncating RBM12 mutation (c.2532delT) segregated with psychosis in a Finnish family (P = 0.020).
• Unaffected carriers of the RBM12 mutation showed similar psychiatric and neuropsychological profiles to schizophrenia patients, indicating incomplete penetrance.

Conclusions:

• RNA-binding-motif protein 12 (RBM12) is a newly identified gene associated with psychosis risk.
• RBM12 mutations provide new insights into the genetic architecture of psychiatric diseases.
• The findings suggest RBM12 plays a role in the pathophysiology of psychosis, even in individuals without a full diagnosis.