Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): Defining novel phenotypes through hierarchical cluster analysis
Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): Defining novel phenotypes through hierarchical cluster analysis
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DOI：
10.1002/humu.20525
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发表时间：
2007-08-01
期刊：
影响因子：
3.9
通讯作者：
Schuelke, Markus
中科院分区：
文献类型：
--
作者：
Guenther, Ulf-Peter;Varon, Raymonda;Schuelke, Markus
常染色体隐性遗传性脊髓性肌萎缩伴呼吸窘迫（SMARD）是一种异质性疾病。免疫球蛋白mu结合蛋白基因（IGHMBP 2）的突变导致SMARDI，但将SMARDI与其他SMARD综合征区分开来的临床标准尚未建立。在这里，我们提出了一个回顾性的临床和遗传学研究，以确定标准，将预测IGHMBP 2突变的存在或不存在。从141例呼吸窘迫和脊髓性肌萎缩表型患者中，我们通过问卷调查记录了临床特征，并对IGHMBP 2的整个编码区进行了测序。在47例（33%）患者中，我们发现了IGHMBP 2突变，其中14例以前没有描述过。通过分层聚类分析发现与IGHMBP 2突变存在相关的临床特征及其组合。该方法通过根据项目的相似性对项目进行分组来检测乍一看不明显的共同特征。结合“6周至6个月之间的呼吸衰竭表现”和（“存在动脉瘤突出”或“早产”）预测IGHMBP 2突变的存在，灵敏度为98%，特异性为92%。非SMARDI患者分为两个不同的症状群，主要由呼吸衰竭时的年龄和是否存在多发性先天性挛缩分开。14个新的IGHMBP 2突变包括错义、移码、剪接位点和无义突变。所有错义突变改变了推定的DNA解旋酶结构域内或附近的保守残基。c.1235+3A>G剪接位点突变并没有完全抑制正确的剪接，我们发现残留的野生型IGHMBP 2 mRNA稳态水平为24.4 +/-6.9%，然而，这不足以避免该患者的SMARD 1。
Autosomal recessive spinal muscular atrophy with respiratory distress (SMARD) is a heterogeneous disorder. Mutations in the immunoglobulin mu-binding protein gene (IGHMBP2) lead to SMARDI, but clinical criteria that delineate SMARDI from other SMARD syndromes are not well established. Here we present a retrospective clinical and genetic study to determine the criteria that would predict the presence or absence of IGHMBP2 mutations. From 141 patients with respiratory distress and a spinal muscular atrophy phenotype we recorded the clinical features through a questionnaire and sequenced the entire coding region of IGHMBP2. In 47 (33%) patients we identified IGHMBP2 mutations, 14 of which were not described before. Clinical features and combinations thereof associated with the presence of IGHMBP2 mutations were discovered through hierarchical cluster analysis. This method detects common traits not evident at first sight by grouping items according to their similarity. The combination of "manifestation of respiratory failure between 6 weeks and 6 months" AND ("presence of diaphragmatic eventration ' OR "preterm birth") predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. Non-SMARDI patients fell into two different symptom clusters, mainly separated by the age at respiratory failure and the presence of multiple congenital contractures. The 14 novel IGHMBP2 mutations comprised missense, frameshift, splice-site, and nonsense mutations. All missense mutations altered conserved residues within or adjacent to the putative DNA helicase domain. The c.1235+3A>G splice-site mutation did not entirely suppress correct splicing and we found a residual wild,type IGHMBP2 mRNA steady-state level of 24.4 +/- 6.9%, which was, however, not sufficient to avert SMARD1 in this patient.