Roifman M, Marcelis C L M, Paton T, Marshall C, Silver R, Lohr J L, Yntema H G, Venselaar H, Kayserili H, van Bon B, Seaward G, Brunner H G, Chitayat D
The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Clin Genet. 2015;87(1):34-41. doi: 10.1111/cge.12401. Epub 2014 May 24.
Robinow Syndrome (RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome (ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway.
鲁宾诺综合征（RS）是一种罕见的骨骼发育不良综合征，其特征为具有类似胎儿面容的畸形特征、中肢短缩、男性外生殖器发育不全以及肾脏和脊柱异常。已报道有常染色体显性和常染色体隐性两种遗传模式。自1969年迈因哈德·鲁宾诺及其同事描述常染色体显性鲁宾诺综合征（ADRS；OMIM 180700）以来，直到最近其分子病因仍不清楚。WNT5A被认为是ADRS的候选基因，因为在两个患病家庭中发现了突变，其中一个是最初描述的索引家庭。我们报告了三个由新的WNT5A杂合突变导致RS的家庭，第一个家庭通过全外显子组测序确认了突变，所有家庭均通过桑格测序得到确认。据我们所知，这是已发表的鉴定出WNT5A突变的ADRS家庭中数量最多的。家庭1和家庭2是受影响家庭成员中首次出现新生突变遗传的病例，因此进一步证明了WNT5A是ADRS的致病基因。最后，我们提出ADRS中WNT5A突变具有特异性，这可能会影响其与Wnt信号通路中其他蛋白质的相互作用。
