Rasmussen Malene B, Nielsen Jakob V, Lourenço Charles M, Melo Joana B, Halgren Christina, Geraldi Camila V L, Marques Wilson, Rodrigues Guilherme R, Thomassen Mads, Bak Mads, Hansen Claus, Ferreira Susana I, Venâncio Margarida, Henriksen Karen F, Lind-Thomsen Allan, Carreira Isabel M, Jensen Niels A, Tommerup Niels
Department of Cellular and Molecular Medicine, Faculty of Health Sciences, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
J Med Genet. 2014 Sep;51(9):605-13. doi: 10.1136/jmedgenet-2014-102535. Epub 2014 Jul 25.
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.
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).
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.
最近，已有一些患者被描述在3q13.31存在结构重排，从而界定了一种具有共同临床特征（包括发育迟缓及其他神经发育障碍（NDD））的新型微缺失综合征。一个最小重叠缺失区域（SRO）涉及五个RefSeq基因，包括转录因子基因ZBTB20和多巴胺受体基因DRD3，被视为该综合征的候选基因。
我们使用阵列比较基因组杂交和新一代配对末端测序来鉴定两名NDD患者中涉及ZBTB20的关键结构重排。在一名患有发育迟缓、注意力缺陷多动障碍、精神病、妥瑞氏综合征和自闭症特征的患者中，一个新生的平衡t(3;18)易位截断了ZBTB20。另一个断点未破坏任何基因。在第二名患有发育迟缓和自闭症的患者中，我们检测到了首例3q13.31微缺失，该缺失截断了ZBTB20，但未涉及DRD3或先前定义的SRO内的其他基因。Zbtb20在发育中的小鼠大脑中直接抑制346个基因。在342个人类直系同源ZBTB20候选靶基因中，我们发现68个与NDD相关。使用染色质免疫沉淀和定量PCR，我们验证了Zbtb20在其中六个基因（Cntn4、Gad1、Nrxn1、Nrxn3、Scn2a、Snap25）的进化保守区域中的体内结合。
我们的研究将ZBTB20的剂量失衡与一系列神经发育、认知和精神疾病联系起来，可能是由多个ZBTB20靶基因的失调介导的，并为3q13.31微缺失综合征中所见NDD的遗传背景提供了新知识。
