Dominant-negative Variants in CBX1 Cause a Neurodevelopmental Disorder.

Purpose: This study aimed to establish variants in CBX1, encoding heterochromatin protein 1 & beta; (HP1 & beta;), as a cause of a novel syndromic neurodevelopmental disorder. Methods: Patients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performed in vitro cellular assays and neurobehavioral and cytological analyses of neuronal cells obtained from newly generated Cbx1 mutant mouse lines. Results: In 3 unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygous de novo variants in CBX1. The identified variants were in the chromodomain, the functional domain of HP1 & beta;, which mediates interactions with chromatin. Cbx1 chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1 & beta; binding to heterochromatin, whereas HP1 & beta; interactome analysis demonstrated that the majority of HP1 & beta;- interacting proteins remained unchanged between the wild-type and mutant HP1 & beta;. Conclusion: These collective findings confirm the role of CBX1 in developmental disabilities through the disruption of HP1 & beta; chromatin binding during neurocognitive development. Because HP1 & beta; forms homodimers and heterodimers, mutant HP1 & beta; likely sequesters wild-type HP1 & beta; and other HP1 proteins, exerting dominant-negative effects. & COPY; 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.