1 Neurobiologisk Forskning, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU2 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU3 Department of Cellular and Molecular Medicine, Faculty of Health Sciences, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.4 University of Säo Paulo5 Laboratório de Citogenética e Genómica and CIMAGO, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.6 Laboratório de Citogenética e Genómica, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.7 Centro Hospitalar e Universitário de Coimbra8 Laboratório de Citogenética e Genómica and CIMAGO, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.9 Neurobiologisk Forskning, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU10 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
BACKGROUND: Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome. METHODS AND RESULTS: We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette's syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20 candidate target genes, we found 68 associated with NDD. Using chromatin immunoprecipitation and quantitative PCR, we validated the in vivo binding of Zbtb20 in evolutionary conserved regions in six of these genes (Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25). CONCLUSIONS: Our study links dosage imbalance of ZBTB20 to a range of neurodevelopmental, cognitive and psychiatric disorders, likely mediated by dysregulation of multiple ZBTB20 target genes, and provides new knowledge on the genetic background of the NDD seen in the 3q13.31 microdeletion syndrome.
Journal of Medical Genetics, 2014, Vol 51, Issue 9, p. 605-613