Unexpected Allelic Heterogeneity and Spectrum of Mutations in Fowler Syndrome Revealed by Next-Generation Exome Sequencing
Unexpected Allelic Heterogeneity and Spectrum of Mutations in Fowler Syndrome Revealed by Next-Generation Exome Sequencing
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DOI：
10.1002/humu.21293
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发表时间：
2010-08-01
期刊：
影响因子：
3.9
通讯作者：
Jabado, Nada
中科院分区：
文献类型：
--
作者：
Lalonde, Emilie;Albrecht, Steffen;Jabado, Nada
蛋白质编码基因约占人类基因组的1%，但含有85%的突变，对疾病相关性状有很大影响。因此，用于选择性测序完整编码区（即，“整个外显子组”）有可能有助于我们对人类疾病的理解。我们使用了一种将Agilent全外显子组捕获与Illumina DNA测序平台相结合的全外显子组测序方法，并研究了来自非血缘家族的两个不相关胎儿，他们患有Fowler综合征（FS），一种定型表型致死性疾病。我们报告了猫白血病病毒亚群C细胞受体家族成员2 FLVCR 2的新种系突变，该突变最近被证明会导致FS。使用这项技术，我们确定了三种类型的遗传异常：点突变，插入-缺失和内含子剪接位点的变化（第一个致病报告使用这项技术），在胎儿谁都是复合杂合子的疾病。虽然揭示了高水平的等位基因异质性和突变谱FS，这项研究进一步说明了成功应用全外显子组测序，以揭示罕见的孟德尔疾病的遗传缺陷。重要的是，我们表明，我们可以使用有限数量的患者（n = 2），在没有共享的遗传遗产和等位基因异质性的存在下，确定罕见，单基因和隐性疾病的基因。Mutat 31：918-923，2010. (C)2010 Wiley-Liss，Inc.
Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., "whole exome'') have the potential to contribute our understanding of human diseases. We used a method for whole-exome sequencing coupling Agilent whole-exome capture to the Illumina DNA-sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular-receptor-family member 2, FLVCR2, which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point-mutations, insertions-deletions, and intronic splice-site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole-exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients (n = 2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity. Hum Mutat 31: 918-923, 2010. (C) 2010 Wiley-Liss, Inc.