Genetic mapping and exome sequencing identify variants associated with five novel diseases.
Genetic mapping and exome sequencing identify variants associated with five novel diseases.
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DOI：
10.1371/journal.pone.0028936
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Strauss KA
中科院分区：
文献类型：
--
作者：
Puffenberger EG;Jinks RN;Sougnez C;Cibulskis K;Willert RA;Achilly NP;Cassidy RP;Fiorentini CJ;Heiken KF;Lawrence JJ;Mahoney MH;Miller CJ;Nair DT;Politi KA;Worcester KN;Setton RA;Dipiazza R;Sherman EA;Eastman JT;Francklyn C;Robey-Bond S;Rider NL;Gabriel S;Morton DH;Strauss KA
特殊儿童诊所(CSC)将生化和分子方法整合到农村儿科实践中，为旧式阿米什人和门诺派(普莱恩)儿童服务。在平原人群中，我们使用单核苷酸多态(SNP)微阵列将隐性疾病遗传定位到包含许多基因的大纯合子单倍型块(平均 = 4.4Mb)(平均 = 79)。对于一些人来说，缺乏信息的图谱或庞大的基因列表排除了通过桑格测序进行疾病基因识别的可能性。布罗德研究所选择了7个这样的条件进行外显子组测序；所有这些条件之前都在CSC使用低密度SNP微阵列结合自合性和连锁分析进行了定位。使用每个疾病1到5个患者样本，我们识别了已知致病基因SLC6A3和FLVCR1中的序列变异，并提供了有力支持TUBGCP6、BRAT1、SNIP1、CRADD和HARS中识别的变异的致病性的证据。我们的结果揭示了新的基因分型技术与特定人群的遗传知识和强大的临床数据相结合的力量。
The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.
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