Language
English
Publication Date
4-1-2025
Journal
Genetics in Medicine
DOI
10.1016/j.gim.2025.101369
PMID
39891528
PMCID
PMC12228429
PubMedCentral® Posted Date
7-5-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Purpose: Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.
Methods: Functional consequences of RYBP variants were assessed using in vitro cellular and in vivo Drosophila melanogaster studies.
Results: We described 7 individuals with heterozygous de novo variants of RYBP and their clinical findings, including severe developmental delay, dysmorphisms, and multiple congenital anomalies. We showed that all single-nucleotide variants in RYBP localize to the N-terminal domain of the gene, which encodes the zinc-finger domain and ubiquitin-binding moiety. In vitro studies have demonstrated that the RYBP c.132C>G p.(Cys44Trp) variant causes reduced protein expression but does not affect the binding of YY1, RING1B, or ubiquitin. In vivo overexpression studies in Drosophila melanogaster showed a dramatic functional difference between human RYBP and its variant forms, affecting the C44 amino acid residue. DNA methylation studies suggested a possible episignature associated with RYBP-related disorder.
Conclusion: Heterozygous de novo variants in RYBP are associated with an identifiable syndromic neurodevelopmental disorder with multiple congenital anomalies.
Keywords
Humans, Neurodevelopmental Disorders, Animals, Drosophila melanogaster, Repressor Proteins, Female, Male, Child, Congenital Abnormalities, Child, Preschool, DNA Methylation, Heterozygote, Polymorphism, Single Nucleotide, Zinc Fingers, neurodevelopment, epigenetic, RYBP, ubiquitin, polycomb
Published Open-Access
yes
Recommended Citation
Weisz-Hubshman, Monika; Burrage, Lindsay C; Jangam, Sharayu V; et al., "De Novo Variants in Rybp Are Associated With a Severe Neurodevelopmental Disorder and Congenital Anomalies" (2025). Faculty and Staff Publications. 4331.
https://digitalcommons.library.tmc.edu/baylor_docs/4331