Episignature Mapping of <i>TRIP12</i> Provides Functional Insight into Clark–Baraitser Syndrome
oleh: Liselot van der Laan, Kathleen Rooney, Mariëlle Alders, Raissa Relator, Haley McConkey, Jennifer Kerkhof, Michael A. Levy, Peter Lauffer, Mio Aerden, Miel Theunis, Eric Legius, Matthew L. Tedder, Lisenka E. L. M. Vissers, Saskia Koene, Claudia Ruivenkamp, Mariette J. V. Hoffer, Dagmar Wieczorek, Nuria C. Bramswig, Theresia Herget, Vanesa López González, Fernando Santos-Simarro, Pernille M. Tørring, Anne-Sophie Denomme-Pichon, Bertrand Isidor, Boris Keren, Sophie Julia, Elise Schaefer, Christine Francannet, Pierre-Yves Maillard, Mala Misra-Isrie, Hilde Van Esch, Marcel M. A. M. Mannens, Bekim Sadikovic, Mieke M. van Haelst, Peter Henneman
| Format: | Article |
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| Diterbitkan: | MDPI AG 2022-11-01 |
Deskripsi
Clark–Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the <i>TRIP12</i> (Thyroid Hormone Receptor Interactor 12) gene. <i>TRIP12</i> 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 <i>TRIP12</i> 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 <i>TRIP12</i>. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic <i>TRIP12</i> 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 <i>TRIP12</i> genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.