The SATB2-associated syndrome (SAS) is an autosomal dominant disorder caused by loss-of-function alterations of SATB2 and characterized by developmental delay/intellectual disability with absent or limited speech development, palatal and dental abnormalities, feeding difficulties, behavioral problems, and discernable facial features. Recently several cases with a balanced chromosomal aberration (BCA) 3’ to SATB2 have been reported. All these individuals present with clinical characteristics of SAS. We therefore hypothesize that these BCAs affect SATB2 regulatory elements and might lead to SATB2 haploinsufficiency. In order to fully understand the functional impact of noncoding structural variation in this locus, a detailed mechanistic dissection of this locus and its constituent functional elements is required. Therefore, we will perform an in-depth functional characterization and validation of the regulatory landscape of SATB2. Furthermore, we will assess the effect of these BCAs on 3D chromatin structure and SATB2 expression. Using this newly gained knowledge, we will subsequently assess the potential of cis-regulation therapy targeting the validated enhancer elements in SAS patient-derived cell lines (i.e. harbouring a pathogenic SATB2 coding variant). Overall, in this project we will determine the regulatory landscape of SATB2 and assess the potential of CRT in this locus for SATB2-associated syndrome.