International Journal of Molecular Sciences (Nov 2022)
Episignature Mapping of <i>TRIP12</i> Provides Functional Insight into Clark–Baraitser Syndrome
- 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
Affiliations
- Liselot van der Laan
- Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Kathleen Rooney
- Department of Pathology and Laboratory Medicine, Western University, London, ON N5A 3K7, Canada
- Mariëlle Alders
- Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Raissa Relator
- Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON N6A 5W9, Canada
- Haley McConkey
- Department of Pathology and Laboratory Medicine, Western University, London, ON N5A 3K7, Canada
- Jennifer Kerkhof
- Department of Pathology and Laboratory Medicine, Western University, London, ON N5A 3K7, Canada
- Michael A. Levy
- Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON N6A 5W9, Canada
- Peter Lauffer
- Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Mio Aerden
- Centre for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
- Miel Theunis
- Centre for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
- Eric Legius
- Centre for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
- Matthew L. Tedder
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Lisenka E. L. M. Vissers
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Saskia Koene
- Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Claudia Ruivenkamp
- Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Mariette J. V. Hoffer
- Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Dagmar Wieczorek
- Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
- Nuria C. Bramswig
- Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
- Theresia Herget
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Vanesa López González
- Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, CIBERER, 30120 Murcia, Spain
- Fernando Santos-Simarro
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, 28029 Madrid, Spain
- Pernille M. Tørring
- Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark
- Anne-Sophie Denomme-Pichon
- UF6254 Innovation en Diagnostic Genomique des Maladies Rares, 21070 Dijon, France
- Bertrand Isidor
- Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France
- Boris Keren
- Department of Medical Genetics, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, 75013 Paris, France
- Sophie Julia
- Service de Génétique Clinique, CHU Toulouse, 31300 Toulouse, France
- Elise Schaefer
- Service de Génétique Clinique, CHU Toulouse, 31300 Toulouse, France
- Christine Francannet
- Service de Genetique Medicale, CHU de Clermont-Ferrand, 63000 Clermont-Ferrand, France
- Pierre-Yves Maillard
- Institut Jérôme Lejeune, 75015 Paris, France
- Mala Misra-Isrie
- Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Hilde Van Esch
- Centre for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
- Marcel M. A. M. Mannens
- Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Bekim Sadikovic
- Department of Pathology and Laboratory Medicine, Western University, London, ON N5A 3K7, Canada
- Mieke M. van Haelst
- Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Peter Henneman
- Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- DOI
- https://doi.org/10.3390/ijms232213664
- Journal volume & issue
-
Vol. 23,
no. 22
p. 13664
Abstract
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.
Keywords
