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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as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood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.

Rare individuals remain cognitively intact despite the presence of neuropathology usually associated with fully symptomatic Alzheimer’s disease (AD), which we refer to as Non-Demented with Alzheimer’s disease Neuropathology (NDAN). Understanding the involved mechanism(s) of their cognitive resistance may reveal novel strategies to treat AD-related dementia. In the pursuit of this goal, we determined the number of hippocampal neural stem cells (NSCs) and investigated the expression of several miRNAs in NDAN and AD subjects. Laser-capture microdissection of autopsy human hippocampus DG and qRT-PCR miRNA analyses were combined with immunofluorescence in this study. The number of SOX2+ NSCs in the DG was significantly increased in NDAN individuals as compared to AD subjects. Further, the prevalence of SOX2+ NSCs was found to correlate with cognitive capacity. Neurogenesis-regulating miRNAs were decreased in NDAN individuals as compared to AD patients. An increased number of NSCs and new neurons in NDAN individuals is associated with a unique expression of regulating miRNAs and strongly support a role of neurogenesis in mediating, in part, the ability of these individuals to resist the pathological burden of AD.