Episignature Mapping of TRIP12 Provides Functional Insight into Clark-Baraitser Syndrome

Clark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the (Thyroid Hormone Receptor Interactor 12) gene. encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzym...

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Veröffentlicht in:International journal of molecular sciences 2022-11, Vol.23 (22), p.13664
Hauptverfasser: van der Laan, Liselot, Rooney, Kathleen, Alders, Mariëlle, Relator, Raissa, McConkey, Haley, Kerkhof, Jennifer, Levy, Michael A, Lauffer, Peter, Aerden, Mio, Theunis, Miel, Legius, Eric, Tedder, Matthew L, Vissers, Lisenka E L M, Koene, Saskia, Ruivenkamp, Claudia, Hoffer, Mariette J V, Wieczorek, Dagmar, Bramswig, Nuria C, Herget, Theresia, González, Vanesa López, Santos-Simarro, Fernando, Tørring, Pernille M, Denomme-Pichon, Anne-Sophie, Isidor, Bertrand, Keren, Boris, Julia, Sophie, Schaefer, Elise, Francannet, Christine, Maillard, Pierre-Yves, Misra-Isrie, Mala, Van Esch, Hilde, Mannens, Marcel M A M, Sadikovic, Bekim, van Haelst, Mieke M, Henneman, Peter
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Sprache:eng
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Zusammenfassung:Clark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the (Thyroid Hormone Receptor Interactor 12) gene. encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in . We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic variants, establishing its utility as a clinical biomarker for Clark-Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232213664