Dominant-negative mutations inCBX1cause a neurodevelopmental disorder

Abstract

The heterochromatin protein 1 (HP1) family of proteins represents an essential structural component of heterochromatin formation and organization. There are three HP1 proteins (HP1α, HP1β, and HP1γ), and HP1β is the only essential HP1 protein during mammalian development. Here we report a neurodevelopmental disorder due to missense mutations in the CBX1 gene which encodes HP1β. Two unrelated individuals were found to have de novo missense mutations in CBX1. Their clinical features include developmental delay, hypotonia and autistic features, suggesting the importance of HP1β in neuronal function. Identified mutations are in a known functional domain, chromodomain, and the identified mutations abolished HP1β-chromatin interactions. Our transcriptome and epigenome analyses revealed that reduced HP1β chromatin affects gene expression of H3K27me3 marked genes, suggesting the importance of HP1β in facultative hetrochromatin organization during human development. This diagnosis represents the first genetic disorder due to germline mutations in genes encoding HP1 proteins.