{Reference Type}: Journal Article
{Title}: DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency.
{Author}: Coenen-van der Spek J;Relator R;Kerkhof J;McConkey H;Levy MA;Tedder ML;Louie RJ;Fletcher RS;Moore HW;Childers A;Farrelly ER;Champaigne NL;Lyons MJ;Everman DB;Rogers RC;Skinner SA;Renck A;Matalon DR;Dills SK;Monteleone B;Demirdas S;Dingemans AJM;Donker Kaat L;Kolk SM;Pfundt R;Rump P;Sadikovic B;Kleefstra T;Butler KM;
{Journal}: Genet Med
{Volume}: 25
{Issue}: 1
{Year}: 01 2023
{Factor}: 8.864
{DOI}: 10.1016/j.gim.2022.10.004
{Abstract}: 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as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.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.