DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency

Jet Coenen-van der Spek; Raissa Relator; Jennifer Kerkhof; Haley McConkey; Michael A Levy; Matthew L Tedder; Raymond J Louie; Robin S Fletcher; Hannah W Moore; Anna Childers; Ellyn R Farrelly; Neena L Champaigne; Michael J Lyons; David B Everman; R Curtis Rogers; Steven A Skinner; Alicia Renck; Dena R Matalon; Shelley K Dills; Berrin Monteleone; Serwet Demirdas; Alexander J M Dingemans; Laura Donker Kaat; Sharon M Kolk; Rolph Pfundt; Patrick Rump; Bekim Sadikovic; Tjitske Kleefstra; Kameryn M Butler

doi:10.1016/j.gim.2022.10.004

DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency

Genet Med. 2023 Jan;25(1):63-75. doi: 10.1016/j.gim.2022.10.004. Epub 2022 Nov 18.

Authors

Jet Coenen-van der Spek¹, Raissa Relator², Jennifer Kerkhof², Haley McConkey³, Michael A Levy², Matthew L Tedder⁴, Raymond J Louie⁴, Robin S Fletcher⁴, Hannah W Moore⁴, Anna Childers⁴, Ellyn R Farrelly⁵, Neena L Champaigne⁴, Michael J Lyons⁴, David B Everman⁴, R Curtis Rogers⁴, Steven A Skinner⁴, Alicia Renck⁶, Dena R Matalon⁶, Shelley K Dills⁷, Berrin Monteleone⁸, Serwet Demirdas⁹, Alexander J M Dingemans¹⁰, Laura Donker Kaat⁹, Sharon M Kolk¹¹, Rolph Pfundt¹, Patrick Rump¹², Bekim Sadikovic¹³, Tjitske Kleefstra¹⁴, Kameryn M Butler¹⁵

Affiliations

¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
² Verspeeten Clinical Genome Centre, London Health Sciences Centre, London Health Sciences Foundation, London, Ontario, Canada.
³ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London Health Sciences Foundation, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
⁴ Greenwood Genetic Center, Greenwood, SC.
⁵ Lucile Packard Children's Hospital Stanford, Palo Alto, CA; Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA.
⁶ Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA.
⁷ Clinical Genetics, Levine Children's Specialty Center, Atrium Health, Charlotte, NC.
⁸ Clinical Genetics, Levine Children's Specialty Center, Atrium Health, Charlotte, NC; Division of Medical Genetics, Department of Pediatrics, NYU Langone Health, NYU Long Island, New York, NY.
⁹ Department of Clinical Genetics, Erasmus Medical Centre, Erasmus University, Rotterdam, The Netherlands.
¹⁰ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹ Department of Molecular Neurobiology, Donders Center for Neuroscience, Faculty of Science, Radboud University, Nijmegen, The Netherlands.
¹² Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹³ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London Health Sciences Foundation, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. Electronic address: bekim.sadikovic@lhsc.on.ca.
¹⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands. Electronic address: Tjitske.Kleefstra@radboudumc.nl.
¹⁵ Greenwood Genetic Center, Greenwood, SC. Electronic address: kbutler@ggc.org.

PMID: 36399132
DOI: 10.1016/j.gim.2022.10.004

Abstract

Purpose: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.

Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples.

Results: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants.

Conclusion: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.

Keywords: DNA methylation; Epigenetics; SIN3A; WITKOS; Witteveen-Kolk syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation* / genetics
Genome
Haploinsufficiency / genetics
Humans
Neurodevelopmental Disorders* / genetics