Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls.
Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls.
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DOI：
10.1093/hmg/ddr589
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发表时间：
2012-04-01
影响因子：
3.5
通讯作者：
Keavney BD
中科院分区：
文献类型：
--
作者：
Soemedi R;Topf A;Wilson IJ;Darlay R;Rahman T;Glen E;Hall D;Huang N;Bentham J;Bhattacharya S;Cosgrove C;Brook JD;Granados-Riveron J;Setchfield K;Bu'lock F;Thornborough C;Devriendt K;Breckpot J;Hofbeck M;Lathrop M;Rauch A;Blue GM;Winlaw DS;Hurles M;Santibanez-Koref M;Cordell HJ;Goodship JA;Keavney BD
染色体1q21.1通过非等位基因同源重组发生的反复重排与表现不完全外显的不同表型相关，包括先天性心脏病(CHD)。然而，∼1Mb关键区内负责每种相关表型的基因仍不清楚。采用单核苷酸多态基因分型芯片(Illumina 660W和Affymetrix 6.0)和多重连接依赖探针扩增技术，对948例法洛四联症(TOF)患者、1488例其他类型CHD患者和6760例正常对照进行了1q21.1基因座检测。我们发现1q21.1重复在TOF患者中比对照组更常见[优势比(OR)30.9，95%可信区间(CI)8.9-107.6；P=2.2×10−7]，但缺失不常见。相反，1q21.1缺失在非TOF冠心病组中比对照组更常见[OR5.5(95%CI 1.4~22.0)；P=0.04]，而重复不常见。在TOF病例中，我们还在1q21.1的临界区内检测到罕见的(n=3)100-200kb重复。这些小重复包含一个共同的基因GJA5，与对照组相比，TOF患者的GJA5基因更加丰富[OR=10.7(95%CI 1.8~64.3)，P=0.01]。这些发现表明，染色体1q21.1的复制和缺失在CHD中表现出一定程度的表型特异性，并暗示GJA5是导致该基因座拷贝数失衡的CHD表型的基因。
Recurrent rearrangements of chromosome 1q21.1 that occur via non-allelic homologous recombination have been associated with variable phenotypes exhibiting incomplete penetrance, including congenital heart disease (CHD). However, the gene or genes within the ∼1 Mb critical region responsible for each of the associated phenotypes remains unknown. We examined the 1q21.1 locus in 948 patients with tetralogy of Fallot (TOF), 1488 patients with other forms of CHD and 6760 ethnically matched controls using single nucleotide polymorphism genotyping arrays (Illumina 660W and Affymetrix 6.0) and multiplex ligation-dependent probe amplification. We found that duplication of 1q21.1 was more common in cases of TOF than in controls [odds ratio (OR) 30.9, 95% confidence interval (CI) 8.9–107.6); P = 2.2 × 10−7], but deletion was not. In contrast, deletion of 1q21.1 was more common in cases of non-TOF CHD than in controls [OR 5.5 (95% CI 1.4–22.0); P = 0.04] while duplication was not. We also detected rare (n = 3) 100–200 kb duplications within the critical region of 1q21.1 in cases of TOF. These small duplications encompassed a single gene in common, GJA5, and were enriched in cases of TOF in comparison to controls [OR = 10.7 (95% CI 1.8–64.3), P = 0.01]. These findings show that duplication and deletion at chromosome 1q21.1 exhibit a degree of phenotypic specificity in CHD, and implicate GJA5 as the gene responsible for the CHD phenotypes observed with copy number imbalances at this locus.
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影响因子：
4
作者：
Mefford, Heather C.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
影响因子：
14.9
作者：
Karolchik, D;Hinrichs, AS;Kent, WJ
通讯作者：
Kent, WJ
影响因子：
15.9
作者：
Morano, M;Zacharzowski, U;Morano, I
通讯作者：
Morano, I
影响因子：
7
作者：
Bailey, JA;Yavor, AM;Eichler, EE
通讯作者：
Eichler, EE
影响因子：
30.8
作者：
Greenway, Steven C.;Pereira, Alexandre C.;Lin, Jennifer C.;DePalma, Steven R.;Israel, Samuel J.;Mesquita, Sonia M.;Ergul, Emel;Conta, Jessie H.;Korn, Joshua M.;McCarroll, Steven A.;Gorham, Joshua M.;Gabriel, Stacey;Altshuler, David M.;Quintanilla-Dieck, Maria de Lourdes;Artunduaga, Maria Alexandra;Eavey, Roland D.;Plenge, Robert M.;Shadick, Nancy A.;Weinblatt, Michael E.;De Jager, Philip L.;Hafler, David A.;Breitbart, Roger E.;Seidman, Jonathan G.;Seidman, Christine E.
通讯作者：
Seidman, Christine E.