Koolen David A, Herbergs Jos, Veltman Joris A, Pfundt Rolph, van Bokhoven Hans, Stroink Hans, Sistermans Erik A, Brunner Han G, Geurts van Kessel Ad, de Vries Bert B A
Department of Human Genetics, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands.
Department of Clinical Genetics, Academic Hospital, Maastricht, The Netherlands.
J Hum Genet. 2006;51(8):721-726. doi: 10.1007/s10038-006-0010-8. Epub 2006 Jul 25.
Holoprosencephaly (HPE) is the most common developmental defect affecting the forebrain and midface in humans. The aetiology of HPE is highly heterogeneous and includes both environmental and genetic factors. Here we report on a boy with mild mental retardation, lobar HPE, epilepsy, mild pyramidal syndrome of the legs, ventricular septal defect, vesicoureteral reflux, preaxial polydactyly, and facial dysmorphisms. Genome-wide tiling path resolution array based comparative genomic hybridisation (array CGH) revealed a de novo copy-number gain at 5q35.1 of 1.24 Mb. Additional multiplex ligation-dependent probe amplification screening of a cohort of 31 patients with HPE for copy-number changes at the 5q35.1 locus did not reveal any additional genomic anomalies. This report defines a novel 1.24 Mb critical interval for HPE and preaxial polydactyly at 5q35.1. The duplicated region encompasses seven genes: RANBP17, TLX3, NPM1, FGF18, FBXW11, STK10, and DC-UbP. Since FBXW11 is relatively highly expressed in fetal brain and is directly involved in proteolytic processing of GLI3, we propose FBXW11 as the most likely candidate gene for the HPE and prexial polydactyly phenotype. Additional research is needed to further establish the role of genes from the 5q35.1 region in brain and limb development and to determine the prevalence of copy number gain in the 5q35.1 region among HPE patients.
全前脑畸形（HPE）是影响人类前脑和中面部的最常见发育缺陷。HPE的病因高度异质性，包括环境和遗传因素。在此，我们报告一名患有轻度智力发育迟缓、叶型HPE、癫痫、轻度腿部锥体束综合征、室间隔缺损、膀胱输尿管反流、轴前多指畸形和面部畸形的男孩。基于全基因组平铺路径分辨率阵列的比较基因组杂交（阵列CGH）显示5q35.1处有1.24 Mb的新生拷贝数增加。对31名HPE患者队列进行的额外多重连接依赖探针扩增筛查，以检测5q35.1位点的拷贝数变化，未发现任何其他基因组异常。本报告定义了一个位于5q35.1的、与HPE和轴前多指畸形相关的新的1.24 Mb关键区间。重复区域包含7个基因：RANBP17、TLX3、NPM1、FGF18、FBXW11、STK10和DC-UbP。由于FBXW11在胎儿脑中相对高表达且直接参与GLI3的蛋白水解加工，我们提出FBXW11是HPE和轴前多指畸形表型最可能的候选基因。需要进一步研究以进一步确定5q35.1区域的基因在脑和肢体发育中的作用，并确定HPE患者中5q35.1区域拷贝数增加的患病率。
