br Discussion br In Conclusion br Declaration of

Discussion
In Conclusion
Declaration of Interests
Authors\' Contributions
Role of the Funding Source
Introduction It is likely that the genetic heterogeneity of the schizophrenia-related psychoses will be pertinent to the development of optimal person-specific treatments. We tested if a set of xpo 1 that had harbored deleterious de novo mutations for schizophrenia in sporadic cases showed other rare missense coding variants in an independent sample that included familial and sporadic cases (Kranz et al., 2015a, 2015b). Next we examined if cases harboring novel or rare variants in these genes, independent of family history, differed in their clinical characteristics. This report describes the phenotypes of subsets of cases with missense coding polymorphisms or novel mutations (“carriers”) in any of four genes that act in different signaling pathways, which have been previously identified and replicated in independent cohorts: These are PTPRG (Protein Tyrosine Phosphatase, Receptor Type G); SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13); TGM5 (Transglutaminase 5); and ARMS/KIDINS220 (Ankyrin Repeat-Rich Membrane-Spanning Protein or Kinase D-Interacting Substrate of 220kDa). These genes are potentially relevant for psychosis. In addition to the presence of rare missense coding polymorphisms and/or novel mutations in a sporadic case in comparison to healthy parents, each gene is highly expressed in the central nervous system, involved in signaling pathways for neuronal network integration, stabilization, and connectivity. Almost a third of the cases in this sample carried rare missense coding polymorphisms or novel mutations in one or more of them (Kranz et al., 2015a, 2015b).
Materials and Methods
Results Fifteen of the 48 cases (31.25%) carried missense coding ultra-rare polymorphisms or novel mutations: 5 in PTPRG, 4 in SLC39A13, 4 in TGM5, and 5 in ARMS/KIDINS220, as previously reported in Kranz et al., (2015a, 2015b). Three carried more than one rare missense coding polymorphism in different genes considered in this analysis: one case harbored PTPRG and SLC39A13 polymorphisms; another harbored rare polymorphisms in both SLC39A13 and ARMS/KIDINS220; and the third case had rare missense coding polymorphisms in ARMS/KIDINS220 and TGM5. The latter case had chronic psychosis but did not meet strict DSM-IV schizophrenia or schizoaffective criteria based on confounding by continuous substance abuse. One PTPRG and one ARMS/KIDINS220 variant carrier did not complete all assessments. As described in the vignettes (appendix) known risk factors for psychosis were common in the carrier cases, including premorbid brain injury, substance abuse, prematurity, and a family history of psychosis. Thyroid disorders were common to all carrier groups, despite none having received lithium pharmacotherapy. Comparing the four carrier groups to non-carrier cases showed no differences in sex, age, or ethnicity. As shown in Table 2, ARMS/KIDINS220 and SLC39A13 variant carriers had lower mean verbal and full scale IQ scores and had more severe general psychopathology symptoms than the other groups. The SLC39A13 variant carriers also had more severe negative symptoms. In addition the PTPRG and SLC39A13 variant carriers cases had an early onset age shown in Table 1. Just one of the SLC39A13 carriers graduated from high school (differing from the non-carriers), whereas all PTPRG carriers with onset after age 17years attained some college education and employment. The SLC39A13 carriers notably had significantly more suicide attempts, whereas no PTPRG or TGM5 carrier made any suicide attempt. Childhood learning disorders, based on the clinical interview reports, were significantly more commonly reported for PTPRG carriers (100%) and significantly less common for TGM5 carriers (0%). Conversely, half of the TGM5 carriers had reported a history of attention deficit disorder, which significantly differed from non-carriers. Depression and substance abuse rates were high in all cases groups. SLC39A13 variant carriers reported the greatest number of medical comorbidities and both they and the ARMS/KIDINS220 variant carriers experienced significantly more degenerative joint disease.