Expanding Clinical and Variant Spectrum of CBX1 ‐Related Syndrome: Report of Three Novel Cases

CBX1-related syndrome is characterized by developmental delay, hypotonia, autistic features, and mild dysmorphic features. This syndrome is caused by heterozygous missense variants in CBX1, which encodes heterochromatin protein 1 beta (HP1β). These variants are situated within the chromodomain of HP1β, a critical region that mediates the interaction between HP1β and trimethylated H3K9. While a prior study identified three individuals with pathogenic CBX1 variants, the variant and clinical spectrum of CBX1-related syndrome remain largely unknown. Here we report three patients with novel de novo heterozygous variants in CBX1. Patients with CBX1 p.(Leu40Pro) and p.(Cys60Arg) manifested with global developmental delay, while the patient with CBX1 p.(Cys60Gly) primarily exhibited speech delay without concurrent motor developmental delay. All variants reside within the chromodomain of the HP1β protein. Interestingly, in vitro cellular assays revealed that the CBX1 p.(Cys60Gly) variant showed an intermediate cellular phenotype between the wild type and the CBX1 p.(Leu40Pro) and p.(Cys60Arg) variants, suggesting a possible genotype-phenotype correlation. This report provides further evidence that missense variants within the chromodomain of HP1β cause a syndromic neurodevelopmental disorder, CBX1-related syndrome.