Clinical and Genetic Heterogeneity in Six Tunisian Families With Horizontal Gaze Palsy With Progressive Scoliosis: A Retrospective Study of 13 Cases
Clinical and Genetic Heterogeneity in Six Tunisian Families With Horizontal Gaze Palsy With Progressive Scoliosis: A Retrospective Study of 13 Cases
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DOI：
10.3389/fped.2020.00172
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发表时间：
2020-04-16
影响因子：
2.6
通讯作者：
Yacoub-Youssef, Houda
中科院分区：
文献类型：
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作者：
Bouchoucha, Sami;Chikhaoui, Asma;Yacoub-Youssef, Houda
背景：进行性脊柱侧凸水平凝视麻痹（HGPPS）是一种罕见的常染色体隐性先天性疾病，其特征是缺乏共轭水平眼球运动，以及儿童和青少年时期进行性衰弱性脊柱侧凸。 HGPPS 与 ROBO3 基因的突变有关。本研究的目的是鉴定突尼斯 HGPPS 患者队列中的致病性变异，并进一步定义 ROBO3 基因型-表型相关性。方法：对来自 6 个无关近亲家庭的 13 名突尼斯患者进行了基因调查，这些患者均表现出 HGPPS。我们使用经典的桑格和全外显子组测序来寻找 HGPPS 的致病变异。结果：在 ROBO3 基因中鉴定出四个不同的纯合突变。其中两个是新发现的纯合突变和非同义突变，通过计算机分析对蛋白质造成有效损害。另外两种突变之前曾在突尼斯 HGPPS 患者中报道过。通过 Sanger 测序对父母和受影响的个体进行了验证。结论：据我们所知，这是迄今为止报告的最大的 HGPPS 家庭中发现 ROBO3 突变的队列。这些分子发现扩展了我们对 ROBO3 突变谱的了解。我们当前研究的相关性有两个：首先是帮助正确治疗脊柱侧弯，其次是保护处于危险中的家庭。
Background: Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) is a rare autosomal recessive congenital disorder characterized by the absence of conjugate horizontal eye movements, and progressive debilitating scoliosis during childhood and adolescence. HGPPS is associated with mutations of the ROBO3 gene. In this study, the objective is to identify pathogenic variants in a cohort of Tunisian patients with HGPPS and to further define ROBO3 genotype-phenotype correlations.Methods: Thirteen Tunisian patients from six unrelated consanguineous families all manifesting HGPPS were genetically investigated. We searched for the causative variants for HGPPS using classical Sanger and whole exome sequencing.Results: Four distinct homozygous mutations were identified in ROBO3 gene. Two of these were newly identified homozygous and non-synonymous mutations, causing effectively damage to the protein by in silico analysis. The other two mutations were previously reported in Tunisian patients with HGPPS. Mutations were validated by Sanger sequencing in parents and affected individuals.Conclusion: To the best of our knowledge, this is the largest ever reported cohort on families with HGPPS in whom ROBO3 mutations were identified. These molecular findings have expanded our knowledge of the ROBO3 mutational spectrum. The relevance of our current study is two-fold; first to assist proper management of the scoliosis and second to protect families at risk.