Episignature Mapping of TRIP12 Provides Functional Insight into Clark-Baraitser Syndrome
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Episignature Mapping of TRIP12 Provides Functional Insight into Clark-Baraitser Syndrome. / 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.
in: INT J MOL SCI, Jahrgang 23, Nr. 22, 13664, 08.11.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Episignature Mapping of TRIP12 Provides Functional Insight into Clark-Baraitser Syndrome
AU - van der Laan, Liselot
AU - Rooney, Kathleen
AU - Alders, Mariëlle
AU - Relator, Raissa
AU - McConkey, Haley
AU - Kerkhof, Jennifer
AU - Levy, Michael A
AU - Lauffer, Peter
AU - Aerden, Mio
AU - Theunis, Miel
AU - Legius, Eric
AU - Tedder, Matthew L
AU - Vissers, Lisenka E L M
AU - Koene, Saskia
AU - Ruivenkamp, Claudia
AU - Hoffer, Mariette J V
AU - Wieczorek, Dagmar
AU - Bramswig, Nuria C
AU - Herget, Theresia
AU - González, Vanesa López
AU - Santos-Simarro, Fernando
AU - Tørring, Pernille M
AU - Denomme-Pichon, Anne-Sophie
AU - Isidor, Bertrand
AU - Keren, Boris
AU - Julia, Sophie
AU - Schaefer, Elise
AU - Francannet, Christine
AU - Maillard, Pierre-Yves
AU - Misra-Isrie, Mala
AU - Van Esch, Hilde
AU - Mannens, Marcel M A M
AU - Sadikovic, Bekim
AU - van Haelst, Mieke M
AU - Henneman, Peter
PY - 2022/11/8
Y1 - 2022/11/8
N2 - Clark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 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 TRIP12 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 TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 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 TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.
AB - Clark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 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 TRIP12 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 TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 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 TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.
KW - Humans
KW - Facies
KW - Mental Retardation, X-Linked
KW - Ubiquitin-Protein Ligases/genetics
KW - Ubiquitin/metabolism
KW - Carrier Proteins/metabolism
U2 - 10.3390/ijms232213664
DO - 10.3390/ijms232213664
M3 - SCORING: Journal article
C2 - 36430143
VL - 23
JO - INT J MOL SCI
JF - INT J MOL SCI
SN - 1661-6596
IS - 22
M1 - 13664
ER -