Multiplex Portuguese families as a lens into rare mutations and the shared genetic architecture of schizophrenia, mood disorders, and autism spectrum disorders

In an analysis of 173 multiplex families from the Portuguese Island Collection (PIC), we characterize the shared genetic architecture of serious mental illnesses (SMI) , including schizophrenia (SZ), bipolar disorder (BP), major depression (MDD), and autism (ASD). Within this cohort, co-segregation of psychotic and mood disorders occurred in 28% of families, while 7% demonstrated co-segregation of intellectual disability or ASD with SZ and mood disorder phenotypes. Whole-genome sequencing (WGS) was performed on a three-generation PIC family to identify rare, large-effect variants. We identified an extremely rare predicted loss-of-function (LoF) mutation in the Chromodomain Helicase DNA Binding Protein 2 (CHD2) gene. These findings highlight the utility of high-density multiplex families in founder populations for identifying rare, large-effect variants that span clinical diagnostic categories, with the identified CHD2 mutation suggesting that variation in a single neurodevelopmental gene may contribute to phenotypic heterogeneity across SMI. By combining population and family-based methodologies, this approach leverages shared genetic backgrounds and environments to provide a unique opportunity for cellular studies to explore the biological mechanisms underlying SMI, offering significant potential to inform future functional research and identify novel therapeutic targets.