Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.
Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.
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Fuchs 内皮性角膜营养不良中 TCF4 内遗传变异的综合评估。
DOI：
10.1167/iovs.14-14958
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发表时间：
2014
影响因子：
4.4
通讯作者：
Baratz,KeithH
中科院分区：
文献类型：
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作者：
Wieben,EricD;Aleff,RossA;Eckloff,BruceW;Atkinson,ElizabethJ;Baheti,Saurabh;Middha,Sumit;Brown,WilliamL;Patel,SanjayV;Kocher,Jean-PierreA;Baratz,KeithH
目的：转录因子4（TCF 4）基因中的单核苷酸变异（SNV）rs613872先前被发现与Fuchs角膜内皮营养不良（FECD）密切相关（P= 6× 10− 26）。随后，发现重复三核苷酸的内含子扩增（TGC）更能预测疾病。我们对TCF 4基因区域进行了全面测序，以鉴定TCF 4内FECD的最佳标记物，并鉴定可能与FECD相关的其他新变体。从68名FECD受试者和16名未受影响的个体中分离白细胞DNA。使用定制捕获组来分离两个先前验证的FECD标志物周围的区域。使用Illumina HiSequation 2000以> 1000×平均覆盖率对TCF 4编码区、内含子和侧翼序列进行测序，跨越465 kb。TGC扩增（> 50个重复）存在于46名（68%）受FECD影响的受试者和1名（6%）正常受试者中。共鉴定出1866个变异体，包括1540个SNV。之前报道的只有两种SNV位于TCF 4编码区，两者都不与疾病分离。没有变异，包括TGC扩增，与疾病状态完全相关。三核苷酸重复序列扩增是一个更好的预测疾病比任何其他变异。TCF 4基因组区域的完整测序显示，FECD没有单一的致病变异体。TCF 4内的内含子三核苷酸重复扩增与FECD的相关性仍然比任何其他遗传变异更强。
Purpose.: The single nucleotide variant (SNV), rs613872, in the transcription factor 4 (TCF4) gene was previously found to be strongly associated (P= 6× 10− 26) with Fuchs' endothelial corneal dystrophy (FECD). Subsequently, an intronic expansion of the repeating trinucleotides, TGC, was found to be even more predictive of disease. We performed comprehensive sequencing of the TCF4 gene region in order to identify the best marker for FECD within TCF4 and to identify other novel variants that may be associated with FECD.Methods.: Leukocyte DNA was isolated from 68 subjects with FECD and 16 unaffected individuals. A custom capture panel was used to isolate the region surrounding the two previously validated markers of FECD. Sequencing of the TCF4 coding region, introns and flanking sequence, spanning 465 kb was performed at> 1000× average coverage using the Illumina HiSequation 2000.Results.: TGC expansion (> 50 repeats) was present in 46 (68%) FECD-affected subjects and one (6%) normal subject. A total of 1866 variants, including 1540 SNVs, were identified. Only two previously reported SNVs resided in the TCF4 coding region, neither of which segregated with disease. No variant, including TGC expansion, correlated perfectly with disease status. Trinucleotide repeat expansion was a better predictor of disease than any other variant.Conclusions.: Complete sequencing of the TCF4 genomic region revealed no single causative variant for FECD. The intronic trinucleotide repeat expansion within TCF4 continues to be more strongly associated with FECD than any other genetic variant.