Genetics in medicine : official journal of the American College of Medical Genetics · 2025
De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Weisz-Hubshman Monika, Burrage Lindsay C, Jangam Sharayu V, Rosenfeld Jill A, von Hardenberg Sandra, Bergmann Anke, Richter Manuela Friederike, Rydzanicz Malgorzata, Ploski Rafal, Stembalska Agnieszka, Chung Wendy K, Hernan Rebecca R, Lim Foong Y, Brunet Theresa, Syrbe Steffen, Keren Boris, Heide Solveig, Murdock David R, Dai Hongzheng, Xia Fan, Ketkar Shamika, Dawson Brian, Narayanan Vinodh, Graves Hillary K, Undiagnosed Diseases Network, Wangler Michael F, Bacino Carlos, Lee Brendan
Аннотация
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.
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.