Candidate gene variant effects on language disorders in Robinson Crusoe Island.
Candidate gene variant effects on language disorders in Robinson Crusoe Island.
复制标题
候选基因变异对鲁滨逊漂流记岛语言障碍的影响。
DOI：
10.1080/03014460.2019.1622776
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发表时间：
2019
影响因子：
1.7
通讯作者：
Mountford HS
中科院分区：
文献类型：
--
作者：
Mountford HS
背景：鲁滨逊漂流记岛是一个地理上和社会上孤立的定居点，位于智利瓦尔帕里索港以西 600 多公里处。据报道，岛民儿童中智利相当于发育性语言障碍（西班牙语，trastorno especico de lenguaje（TEL））的发病率异常高（30%），其中 90% 的受影响儿童是一对最初创始人兄弟的直系后裔，因此强烈表明存在共同的遗传基础。 目的：本研究报告了对 34 个先前直接涉及语言相关机制的基因的全面检查。它利用全基因组测序来研究 7 名受 TEL 影响的岛民和 10 名未受影响的岛民的潜在潜在变异。目的是确定两种遗传模型范式下 TEL 表型的潜在遗传原因；孟德尔单基因和复杂易感性。 主题和方法：使用有针对性的候选基因方法来寻找罕见的、共享的变异，这些变异可能是孟德尔遗传模型中 TEL 诊断的基础。这项研究测试了受 TEL 影响的个体或与创始人兄弟血统相关的岛民中罕见变异的总体负担是否丰富。它进一步检查是否有任何变异与情感状态或创始人兄弟相关状态分离，因此，作为复杂模型的一部分，可能会增加患语言障碍的风险。最后，进行基于基因的测试来评估候选基因的组合变异与 TEL 影响状态之间的关系。结果：在 34 个候选基因中，没有单一致病性罕见变异与影响或创始人相关状态分离。此外，没有发现证据表明与 TLD 个体相比，TEL 个体的变异负担总体增加。基于基因的分析发现，34 个基因的变异的综合影响与情感状态或创始人兄弟相关性之间没有明确的关联。结论：鲁滨逊漂流记岛上发现的语言障碍的高患病率不是由共享的高影响力变异引起的，也不是由先前与语言障碍有关的候选基因内的变异负担增加引起的。我们对与语言障碍有关的基因中的“容易实现的目标”进行了全面测试。因此，《鲁宾逊漂流记》中 TEL 的根本原因在于这些已知的语言障碍基因之外，或者在复杂的易感性模型中。
Background:Robinson Crusoe Island is a geographically and socially isolated settlement located over 600 km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (in Spanish,trastorno especifico de lenguaje(TEL)), has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis.Aim:This study reports a comprehensive examination of 34 genes that have been previously directly implicated in language-related mechanisms. It utilises whole-genome sequencing to investigate potential underlying variants in seven TEL affected and 10 unaffected islanders. The aim was to identify the underlying genetic cause of the TEL phenotype under two inheritance model paradigms; Mendelian monogenic and complex susceptibility.Subjects and methods:A targeted candidate gene approach was used to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. This study tested whether an overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage. It further examined if any variants segregate with affection status or with founder-brother-related status and, therefore, may increase risk of developing a language disorder as part of a complex model. Finally, gene-based tests were performed to evaluate relationships between combined variation across candidate genes and TEL affection status.Results:No single pathogenic rare variant segregated with either affection or founder-related status within the 34 candidate genes. Additionally, no evidence was found of an overall increased variant burden in TEL individuals compared to those with TLD. Gene-based analysis found no clear association between the combined effects of variants across the 34 genes and affection status or founder-brother-relatedness.Conclusion:The high prevalence of language disorders found on Robinson Crusoe Island is not caused by either a shared high-impact variant, or an increased burden of variants within candidate genes previously implicated in language disorders. We have comprehensively tested for ‘low hanging fruit’ in genes implicated in language disorders. Therefore, the underlying cause of TEL on Robinson Crusoe lies outside of these known language disorder genes, or within a complex susceptibility model.