Author(s):
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Witteveen, J.S.
;
Willemsen, M.H.
; Dombroski, T.C.; Bakel, N.H. van; Nillesen, W.M.;
Hulten, J.A. van
; Jansen, E.J.; Verkaik, D.; Veenstra-Knol, H.E.;
Ravenswaaij-Arts, C.M.A. van
; Wassink-Ruiter, J.S.; Vincent, M.; David, A.; Le Caignec, C.; Schieving, J.; Gilissen, C.; Foulds, N.; Rump, P.; Strom, T.; Cremer, K.; Zink, A.M.; Engels, H.;
Munnik, S.A. de
;
Visser, J.E.
;
Brunner, H.G.
; Martens, G.J.;
Pfundt, R.P.
;
Kleefstra, T.
;
Kolk, S.M.
|
Subject:
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Molecular Animal Physiology Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences |
Organization:
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Molecular Animal Physiology Human Genetics Primary and Community Care Cognitive Neuroscience Radboudumc Extern Neurology Molecular Neurobiology |
Abstract:
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Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.
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