The expanding spectrum of COL2A1 gene variants IN136 patients with a skeletal dysplasia phenotype
The expanding spectrum of COL2A1 gene variants IN136 patients with a skeletal dysplasia phenotype
复制标题
DOI：
10.1038/ejhg.2015.250
复制
发表时间：
2016-07-01
影响因子：
5.2
通讯作者：
Touitou, Isabelle
中科院分区：
文献类型：
--
作者：
Barat-Houari, Mouna;Dumont, Bruno;Touitou, Isabelle
杂合COL 2A 1变体引起广泛的骨骼发育不良，称为II型胶原病。我们在法国系列中评估了这种基因的影响。在桑格测序进行分子诊断之前，应用决策树选择136例先证者（71例Stickler病例，21例先天性脊椎骨骺发育不良病例，11例最严重的发育不良病例和34例其他发育不良病例）。我们在71名阳性患者中鉴定出66种不同的变异。在这些患者中，18人属于多重家庭，53人为散发。大多数变异体（38/44，86%）位于胶原蛋白链的三螺旋结构域，甘氨酸取代主要见于重度表型，而精氨酸至半胱氨酸的变化更常见于中度表型。这一系列骨骼发育不良是迄今为止报道的最大的骨骼发育不良之一，在已发表的数据中增加了44种新的变异（15%）。我们已经证实，大约一半的Stickler患者（46%）携带COL 2A 1变异体，并且分子谱在表型中不同。为了进一步解决基因型-表型相关性的问题，我们计划使用靶向的下一代测序方法来筛选我们的患者的其他候选基因。
Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.