Expanding clinical and variant spectrum of CBX1-related syndrome: Report of three novel cases
- 1Univ of Tx Sw Medical Ctr
Abstract
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 (HP1{beta}). These variants are situated within the chromodomain of HP1{beta}, a critical region that mediates the interaction between HP1{beta} and trimethylated H3K9. While a prior study identified three individuals with pathogenic CBX1 variants, the variant and clinical spectrum of CBX1-related syndrome remains 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 chromodomain of the HP1{beta} protein. Interestingly, in vitro cellular assays revealed that 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 HP1{beta} cause a syndromic neurodevelopmental disorder, CBX1-related syndrome.
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BibTeX
@misc{carrollo2026expanding,
title = {{Expanding clinical and variant spectrum of CBX1-related syndrome: Report of three novel cases}},
author = {G. Carrollo and S. Fujino and H. Higgs and A. Kabahizi and R. Le and R. Rabin and J. Pappas and A. Crunk and K. Ranguin and J. Mortreux and AURAGEN consortium and M. Lackmy and C. A. Gadia and M. H. K. Chau and J. A. Rosenfeld and X. Luo and K. Izumi},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.26363820},
url = {https://www.medrxiv.org/content/10.64898/2026.09.28.26363820v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Expanding clinical and variant spectrum of CBX1-related syndrome: Report of three novel cases
AU - G. Carrollo
AU - S. Fujino
AU - H. Higgs
AU - A. Kabahizi
AU - R. Le
AU - R. Rabin
AU - J. Pappas
AU - A. Crunk
AU - K. Ranguin
AU - J. Mortreux
AU - AURAGEN consortium
AU - M. Lackmy
AU - C. A. Gadia
AU - M. H. K. Chau
AU - J. A. Rosenfeld
AU - X. Luo
AU - K. Izumi
PY - 2026
DA - 2026/09/28
PB - medRxiv
DO - 10.64898/2026.09.28.26363820
UR - https://www.medrxiv.org/content/10.64898/2026.09.28.26363820v1
AB - 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 (HP1{beta}). These variants are situated within the chromodomain of HP1{beta}, a critical region that mediates the interaction between HP1{beta} and trimethylated H3K9. While a prior study identified three individuals with pathogenic CBX1 variants, the variant and clinical spectrum of CBX1-related syndrome remains 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 chromodomain of the HP1{beta} protein. Interestingly, in vitro cellular assays revealed that 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 HP1{beta} cause a syndromic neurodevelopmental disorder, CBX1-related syndrome.
ER -