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

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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.

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