Barat-Houari Mouna, Dumont Bruno, Fabre Aurélie, Them Frédéric Tm, Alembik Yves, Alessandri Jean-Luc, Amiel Jeanne, Audebert Séverine, Baumann-Morel Clarisse, Blanchet Patricia, Bieth Eric, Brechard Marie, Busa Tiffany, Calvas Patrick, Capri Yline, Cartault François, Chassaing Nicolas, Ciorca Vidrica, Coubes Christine, David Albert, Delezoide Anne-Lise, Dupin-Deguine Delphine, El Chehadeh Salima, Faivre Laurence, Giuliano Fabienne, Goldenberg Alice, Isidor Bertrand, Jacquemont Marie-Line, Julia Sophie, Kaplan Josseline, Lacombe Didier, Lebrun Marine, Marlin Sandrine, Martin-Coignard Dominique, Martinovic Jelena, Masurel Alice, Melki Judith, Mozelle-Nivoix Monique, Nguyen Karine, Odent Sylvie, Philip Nicole, Pinson Lucile, Plessis Ghislaine, Quélin Chloé, Shaeffer Elise, Sigaudy Sabine, Thauvin Christel, Till Marianne, Touraine Renaud, Vigneron Jacqueline, Baujat Geneviève, Cormier-Daire Valérie, Le Merrer Martine, Geneviève David, Touitou Isabelle
Laboratoire de génétique des maladies rares et auto-inflammatoires, CHRU, Montpellier, France.
Génétique des Maladies Auto-inflammatoires et des Ostéo-arthropathies chroniques, INSERM U1183, Montpellier, France.
Eur J Hum Genet. 2016 Jul;24(7):992-1000. doi: 10.1038/ejhg.2015.250. Epub 2015 Dec 2.
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.
COL2A1基因杂合变异可导致一系列广泛的骨骼发育不良，称为II型胶原病。我们评估了该基因在我们法国队列中的影响。在通过桑格测序进行分子诊断之前，应用决策树选择了136名先证者（71例Stickler综合征患者、21例先天性脊椎骨骺发育不良患者、11例Kniest发育不良患者和34例其他发育不良患者）。我们在71例阳性患者中鉴定出66种不同的变异。在这些患者中，18例属于复合家庭，53例为散发病例。大多数变异（38/44，86%）位于胶原链的三螺旋结构域，甘氨酸替代主要出现在严重表型中，而精氨酸到半胱氨酸的变化在中度表型中更常见。这一系列骨骼发育不良是迄今为止报道的最大系列之一，为已发表的数据增加了44种新变异（15%）。我们已经证实，约一半的Stickler综合征患者（46%）携带COL2A1变异，并且分子谱在不同表型中有所不同。为了进一步解决基因型-表型相关性问题，我们计划使用靶向二代测序方法对我们的患者进行其他候选基因筛查。
