LAUSR

Abstract The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. It is a multisystem congenital anomaly disorder characterized by variable manifestations including high rates of neuropsychiatric disorders. A unique 22q11.2DS multigeneration family was studied. Variability of psychiatric phenotypes in the affected family members (mother and her four children), including psychotic and non-psychotic subjects, enabled us to attempt to identify genetic risk factors that contribute to psychotic disorder and schizophrenia (SZ). Comparative genomic hybridization (CGH) array identified 15 CNVs outside the 22q11.2 region, and two of them defined as rare. De novo CNVs were detected only in the severe psychotic siblings (SZ and delusional disorder). These findings support the de novo mutation theory of SZ. The 22q11.2 haplotype analysis based on whole exome sequencing (WES) identified two haplotype variants for the four 22q11.2DS siblings: one for the three psychotic siblings termed by us as a "psychosis" risk haplotype and the other for the non-psychotic sister, a putative "protective" haplotype. WES enabled us to search for additional genetic variants outside 22q11.2 region using two approaches: 1) search for de novo mutations and recessive alleles for the SZ individual; 2) search for variants that are common to the psychotic siblings as well as variants that are unique to the SZ individual, using the Venn model. Bioinformatic analyses of CGH array, WES and 22q11.2 haplotype construction resulted in identifying de novo, rare, conserved and "damaging" genetic variants involved in cellular pathways relevant to neurodevelopmental disorders that may contribute to the psychotic phenotype in this 22q11.2 family. Such multi-affected families with phenotypic variability can assist in identification of genetic risk variants that contribute to the susceptibility to develop psychosis in 22q11.2DS that may also be relevant to SZ in general.