Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13
Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13
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DOI：
10.1093/hmg/ddq569
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发表时间：
2011-04-01
影响因子：
3.5
通讯作者：
Ober, Carole
中科院分区：
文献类型：
--
作者：
Caliskan, Minal;Chong, Jessica X.;Ober, Carole
外显子组测序是发现孟德尔疾病基因的强大工具。此前，我们报道了一个近亲家族中常染色体隐性遗传性非综合征性智力低下 (NSMR) 的新位点 [Nolan, D. K.、Chen, P.、Das, S.、Ober, C. 和 Waggoner, D. (2008) 染色体 19p13 上非综合征性智力低下位点的精细定位。是。 J. Med。热内特. A，146A，1414-1422]。使用连锁和纯合性作图，我们之前将该基因定位于染色体 19p13。该同胞的父母最近被纳入一个外显子组测序项目。使用一系列过滤器，我们将假定的因果突变缩小到与 NSMR 分离的单个变异位点：该突变在 5 个受影响的兄弟姐妹中是纯合的，但在 8 个未受影响的兄弟姐妹中没有一个是纯合的。该突变导致 TECR（反式 2,3-烯酰辅酶A 还原酶）（一种突触糖蛋白）中第 182 位氨基酸处的高度保守的脯氨酸被亮氨酸取代。我们的结果揭示了大规模并行测序对于识别使用传统方法无法找到的新疾病基因的价值，并且仅识别了常染色体隐性遗传 NSMR 的第七个因果突变。
Exome sequencing is a powerful tool for discovery of the Mendelian disease genes. Previously, we reported a novel locus for autosomal recessive non-syndromic mental retardation (NSMR) in a consanguineous family [Nolan, D. K., Chen, P., Das, S., Ober, C. and Waggoner, D. (2008) Fine mapping of a locus for nonsyndromic mental retardation on chromosome 19p13. Am. J. Med. Genet. A, 146A, 1414-1422]. Using linkage and homozygosity mapping, we previously localized the gene to chromosome 19p13. The parents of this sibship were recently included in an exome sequencing project. Using a series of filters, we narrowed the putative causal mutation to a single variant site that segregated with NSMR: the mutation was homozygous in five affected siblings but in none of eight unaffected siblings. This mutation causes a substitution of a leucine for a highly conserved proline at amino acid 182 in TECR (trans-2,3-enoyl-CoA reductase), a synaptic glycoprotein. Our results reveal the value of massively parallel sequencing for identification of novel disease genes that could not be found using traditional approaches and identifies only the seventh causal mutation for autosomal recessive NSMR.