Clinical and mutational spectrum of Mowat-Wilson Syndrome
Clinical and mutational spectrum of Mowat-Wilson Syndrome
复制标题
DOI：
10.1016/j.ejmg.2005.01.003
复制
发表时间：
2005-04-01
影响因子：
1.9
通讯作者：
Rauch, A
中科院分区：
文献类型：
--
作者：
Zweier, C;Thiel, CT;Rauch, A
Mowat-Wilson综合征是最近描述的精神发育迟滞综合征，通常与多种畸形和可识别的面部表型有关，其由转录抑制因子ZFHXIB的缺陷引起。为了解决临床和突变变异性的问题，我们分析了大量疑似Mowat-Wilson综合征（MWS）的患者。在不了解其突变状态的情况下，根据面部表型将70例患者分为“典型MWS”、“模糊”和“非典型”组。使用FISH、qPCR和测序，在所有28例归类为典型MWS的患者中检测到ZFHXIB缺失、剪接位点或截短突变。其余15例面部特征不明确或27例不典型患者中无明显ZFHXIB缺陷。基因型-表型分析证实，ZFHXIB缺失和终止突变导致可识别的面部畸形，并伴有严重的精神发育迟滞和各种畸形，如先天性巨结肠和先天性心脏病。我们的研究结果表明，结构性眼异常，如小眼，应被视为MWS光谱的一部分。我们还发现胼胝体发育不全和泌尿生殖系统异常（尤其是尿道下裂）是ZFHXIB缺陷的显著阳性预测因子。根据我们对受影响的兄弟姐妹的观察和先前报道的MWS病例数，我们认为复发风险约为1%。MWS和MWS样患者中缺乏错义突变表明可能存在与该转录因子错义突变相关的其他尚未识别的表型。(c)2005年，Elsevier SAS。All rights reserved.
Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHXIB. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHXIB deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHXIB defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHXIB deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHXIB defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor. (c) 2005 Elsevier SAS. All rights reserved.