Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.
Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.
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DOI：
10.1038/srep46105
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发表时间：
2017-04-25
影响因子：
4.6
通讯作者：
Fisher SE
中科院分区：
文献类型：
--
作者：
Chen XS;Reader RH;Hoischen A;Veltman JA;Simpson NH;Francks C;Newbury DF;Fisher SE
尽管有足够的智力和机会，但仍有相当一部分儿童在获得熟练的语言技能方面存在无法解释的问题。发育性语言障碍具有很高的遗传性，具有重大的社会影响。分子研究已经开始确定候选基因座，但大部分潜在的遗传结构仍未确定。我们对43个患有严重特定语言障碍的无关先证者进行了全外显子测序，然后用Sanger测序进行了独立验证，并分析了父母和兄弟姐妹的分离模式，以期为病因学提供新的线索。通过首先关注文献中预定义的一组已知候选基因，我们确定了已经与多种语言相关综合征有关的基因中潜在的致病变异，包括ERC1、GRIN2A和SRPX2。互补分析提示新的假定候选基因携带被预测具有功能效应的有效变体，如OXR1、SCN9A和KMT2D。我们还搜索了潜在的“多重命中”病例；一个先证者携带罕见的AUTS2变体和罕见的影响STARD9的遗传单倍型，而另一个先证者携带SEMA6D的新的非同义变体和SYNPR的罕见的止损收益。在将范围扩大到所有稀有和新的外显子体变体上，我们确定了丰富这些变体的生物学主题，包括微管运输和细胞骨架调节。
A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.