%0 Journal Article
%T DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency.
%A Coenen-van der Spek J
%A Relator R
%A Kerkhof J
%A McConkey H
%A Levy MA
%A Tedder ML
%A Louie RJ
%A Fletcher RS
%A Moore HW
%A Childers A
%A Farrelly ER
%A Champaigne NL
%A Lyons MJ
%A Everman DB
%A Rogers RC
%A Skinner SA
%A Renck A
%A Matalon DR
%A Dills SK
%A Monteleone B
%A Demirdas S
%A Dingemans AJM
%A Donker Kaat L
%A Kolk SM
%A Pfundt R
%A Rump P
%A Sadikovic B
%A Kleefstra T
%A Butler KM
%J Genet Med
%V 25
%N 1
%D 01 2023
%M 36399132
%F 8.864
%R 10.1016/j.gim.2022.10.004
%X 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as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.<BR>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.<BR>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.<BR>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.