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Background Schizophrenia (SCZ) is a debilitating mental illness characterized by a highly complex, heterogeneous, non-mendelian genetic background. Recent progress in dissecting genetic architecture of SCZ has accelerated over the last decade due to new advanced technologies. Genome-Wide Association Studies (GWAS) on extremely large samples of patients identified and replicated hundreds of Single-Nucleotide Polymorphism (SNPs), each exhibiting only a modest effect. The analysis of genomic Copy Number Variations (CNVs) clarified the role of rare structural variants conferring significant risk by disrupting multiple genes involved in neurodevelopmental pathways, and linked to SCZ. In this scenario, the aim of our study is to carry out a genetic characterization of a cohort of patients affected by SCZ, in order to assess the risk of recurrence, to elucidate putative pathogenetic mechanisms and, whenever possible, to conceive tailored interventions and therapies. Methods 34 patients (8 women and 26 men) affected by SCZ and admitted to Day Hospital at Psychiatric Division for Treatment Resistant Psychosis of the University of Naples Federico II were recruited, and underwent: i) psychopathological evaluation and assessment of clinical response to antipsychotics; ii) genetic counseling; iii) further diagnostic investigation by using Comparative Genomic Hybridization (CGH) + Single Nucleotide Polymorphism (SNP) microarray with 2x400k Agilent’s platform “GenetiSure” for detecting unbalanced chromosomal abnormalities and regions of homozygosity (ROHs). Results Structural pathogenetic rearrangements resulted in 9 (27%) patients. Those identified were the following: 15q13.3 deletion, 16p13.11 duplication, 22q11.22 deletion (TOP3B), 22q11.22 (PRODH, DGCR5, DGCR6), RBFOX1 deletion, TCF4 deletion, derivative X chromosome (X;Y translocation). Potentially pathogenic rearrangements, involving genes associated with psychiatric disorders or implicated in neurodevelopment, resulted in 15 patients (44%). No relevant CNVs were detected in 10 patients (29%), although they showed the presence of ROHs that may contain susceptibility loci, since many neurodevelopmental genes map onto or near these specific regions. Certain of these rearrangements occur in many patients, and certain patients showed likewise multiple rearrangements. Discussion The analysis of CNVs and SNPs allowed us to characterize the genetic disease structure in the whole cohort of patients and helped to refine the diagnosis in a few cases, thereby ascertaining an underlying specific genetic condition. A further extension of the study, in terms of sample size and more accurate investigations (i.e genetic mapping of ROHs) is underway. According to literature, rare risk-associated CNVs account for 2% of SCZ cases, but their higher prevalence (27%) in our sample may be influenced by a larger percentage of Treatment Resistant and more severely ill patients (since they were recruited in a highly specialized Unit for Treatment Resistant Psychosis). Therefore, our future purpose is to demonstrate a robust genetic modulation of Treatment Resistant endophenotypes of SCZ. Moreover, we believe that the role of genetic counseling in psychiatric services should be emphasized, and that genetic testing in this field should not be restricted to suspected childhood neuropsychiatric disorders. According to the neurodevelopmental hypothesis of SCZ, that suggests a brain development disruption in early life (due to genetic and early environmental factors), prompting to a subsequent later emergence of the disease in adulthood, even chronic complex adult mental illness, such as SCZ, deserves detailed investigations and a more exhaustive genetic evaluation.

schizophrenia bulletin

M170. GENETIC CHARACTERIZATION OF A COHORT OF PATIENTS AFFECTED BY SCHIZOPHRENIA. THE ROLE FOR RARE STRUCTURAL VARIANTS IN MODULATING TREATMENT RESISTANT ENDOPHENOTYPES: PRELIMINARY DATA