© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. NATURE GENETICS ADVANCE ONLINE PUBLICATION 1 LETTERS Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole- genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T (P = 2.2 × 10 -4 ), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis (P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile (P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease. Patients with schizophrenia have severely reduced fecundity 1 . Therefore, sequence variants having a strong effect on the disease are expected to be de novo or recent. Current data suggest that, in comparison to individuals with autism or intellectual disability, a smaller fraction of patients with schizophrenia have their disease rooted in de novo mutations 2,3 . Instead, patients with schizophrenia may carry a surplus of ultra-rare mutations, estimated to be on average a few generations old 2 . A family-based study design is a powerful way to investigate these variants; however, most recent, large-scale studies of rare variants in schizophrenia have used case–control 2–4 or de novo 3,5 approaches. Here we examine an Icelandic family that is highly enriched for psychosis, having six individuals with schizophrenia, two with schizoaf- fective disorder and two with psychotic bipolar disorder, each of whom is descended from a founder couple (Fig. 1 and Supplementary Table 1). We performed chip typing, followed by long-range phas- ing, for all ten patients and whole-genome sequencing for seven of the patients. Using a novel statistical procedure (Online Methods), we investigated the within-family association of very rare (carrier frequency < 0.1%) nonsynonymous or splice-site variants with psychosis. Exactly one variant, a nonsense mutation in RBM12 (NM_001198838.1:c.2377G>T or NP_001185767.1:p.Gly793*) that was carried by all ten individuals with psychosis, showed significant association with psychosis (genome-wide P = 2.2 × 10 -4 ). RBM12 c.2377G>T is not found in gnomAD 6 (n = 138,632), and, in the Icelandic whole-genome sequencing data set (n = 28,075), all carriers of the variant (n = 21) are descendants of A1 and A2 (Fig. 1). Icelandic parent-of-origin data place the mutation on a chromosome inherited from A1. To determine whether A1 was the earliest carrier of the mutation, we searched for whole-genome-sequenced individuals outside of the family who shared the haplotype harboring the mutation. We found that an offspring of a half-sibling of A1 carried the haplotype but did not harbor c.2377G>T (Supplementary Figs. 1 and 2). Sanger sequencing showed that four offspring of a second half-sibling of A1 also carried the haplotype but lacked the variant (Supplementary Figs. 1 and 2). Thus, the mutation most likely occurred during game- togenesis in the father of A1 (Supplementary Fig. 1). As the c.2377G>T variant is found in the 3′ part of the only coding (and terminal) exon of RBM12, transcripts containing c.2377G>T are not predicted to undergo nonsense-mediated decay 7 . We used Epstein–Barr virus (EBV)-transformed lymphoblasts derived from lymphocytes from five carriers and five non-carriers to confirm that a stable, truncated protein is expressed exclusively in carriers (Fig. 2a and Supplementary Fig. 3). The domain structure predicted for the RBM12 protein 8 suggests that the truncated form retains two internal RNA-recognition motifs (RRMs) but loses a third, terminal RRM (Fig. 2b). Truncating mutations in RBM12 are associated with psychosis Stacy Steinberg 1 , Steinunn Gudmundsdottir 1 , Gardar Sveinbjornsson 1 , Jaana Suvisaari 2 , Tiina Paunio 2,3 , Minna Torniainen-Holm 2,4 , Michael L Frigge 1 , Gudrun A Jonsdottir 1 , Johanna Huttenlocher 1,5 , Sunna Arnarsdottir 1,6 , Oddur Ingimarsson 6,7 , Magnus Haraldsson 6,7 , Thorarinn Tyrfingsson 8 , Thorgeir E Thorgeirsson 1 , Augustine Kong 1 , Gudmundur L Norddahl 1 , Daniel F Gudbjartsson 1 , Engilbert Sigurdsson 6,7 , Hreinn Stefansson 1 & Kari Stefansson 1,7 1 deCODE Genetics/Amgen, Reykjavik, Iceland. 2 National Institute for Health and Welfare (THL), Helsinki, Finland. 3 Department of Psychiatry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 4 Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland. 5 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 6 Department of Psychiatry, Landspitali, National University Hospital, Reykjavik, Iceland. 7 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 8 National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland. Correspondence should be addressed to K.S. (kstefans@decode.is). Received 12 January; accepted 12 May; published online 19 June 2017; doi:10.1038/ng.3894