Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.
Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.
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先天性心脏病患者的染色体微阵列检测揭示了新的致病位点和高诊断率
DOI：
10.1186/1471-2164-15-1127
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发表时间：
2014-12-17
期刊：
影响因子：
4.4
通讯作者：
Shen Y
中科院分区：
文献类型：
--
作者：
Geng J;Picker J;Zheng Z;Zhang X;Wang J;Hisama F;Brown DW;Mullen MP;Harris D;Stoler J;Seman A;Miller DT;Fu Q;Roberts AE;Shen Y
背景先天性心脏缺陷（CHD）作为最常见的先天性异常，常与致病性拷贝数变异（CNVs）相关。目前，冠心病患者通常接受染色体微阵列（CMA）检测，但CMA对冠心病患者的诊断率尚未基于大型患者队列进行广泛评估。在这项研究中，我们回顾性地评估了514例冠心病患者（来自波士顿儿童医院（BCH）的422例临床队列和来自上海儿童医学中心（SCMC）的92例研究队列）中检测到的CNVs，并进行了基因型-表型分析。此外，通过整合几种工具和公共数据源，对新型冠心病候选基因鉴定中包含的致病性/可能致病性CNVs中的基因进行优先排序。结果基于BCH队列，CMA检测对冠心病患者的总体诊断率为12.8%（致病性CNVs）-18.5%（致病性和可能致病性CNVs）。CMA对综合征型冠心病的诊断率为14.1-20.6%（不包括非整倍体病例），而对孤立型冠心病的诊断率为4.3-9.3%。4个复发基因位点（4q末端区，15q11.2, 16p12.2和Yp11.2）在病例中比对照组显著富集。这些区域被认为是新的冠心病位点。通过基因优先级分析，我们进一步确定了20个基因作为最有可能的新型冠心病候选基因。结论本研究CMA具有较高的临床诊断率，为CMA作为冠心病患者的一线遗传诊断工具提供了支持证据。在我们的研究中检测到的CNVs提示了一些值得进一步研究的冠心病候选基因。
BackgroundCongenital heart defects (CHD), as the most common congenital anomaly, have been reported to be frequently associated with pathogenic copy number variants (CNVs). Currently, patients with CHD are routinely offered chromosomal microarray (CMA) testing, but the diagnostic yield of CMA on CHD patients has not been extensively evaluated based on a large patient cohort. In this study, we retrospectively assessed the detected CNVs in a total of 514 CHD cases (a 422-case clinical cohort from Boston Children's Hospital (BCH) and a 92-case research cohort from Shanghai Children’s Medical Center (SCMC)) and conducted a genotype-phenotype analysis. Furthermore, genes encompassed in pathogenic/likely pathogenic CNVs were prioritized by integrating several tools and public data sources for novel CHD candidate gene identification.ResultsBased on the BCH cohort, the overall diagnostic yield of CMA testing for CHD patients was 12.8(pathogenic CNVs)-18.5% (pathogenic and likely pathogenic CNVs). The diagnostic yield of CMA for syndromic CHD was 14.1-20.6% (excluding aneuploidy cases), whereas the diagnostic yield for isolated CHD was 4.3-9.3%. Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls. These regions are considered as novel CHD loci. We further identified 20 genes as the most likely novel CHD candidate genes through gene prioritization analysis.ConclusionThe high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients. The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation.
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DOI：
10.1097/gim.0b013e3181f8baad
发表时间：
2010-11
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Manning M;Hudgins L;Professional Practice and Guidelines Committee
通讯作者：
Professional Practice and Guidelines Committee
影响因子：
3.3
作者：
Pomies, Pascal;Pashmforoush, Mohammad;Beckerle, Mary C.
通讯作者：
Beckerle, Mary C.
影响因子：
20.1
作者：
Fahed AC;Gelb BD;Seidman JG;Seidman CE
通讯作者：
Seidman CE
影响因子：
9.8
作者：
Miller, David T.;Adam, Margaret P.;Ledbetter, David H.
通讯作者：
Ledbetter, David H.
DOI：
10.1097/gim.0b013e31822c79f9
发表时间：
2011-09
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Kaminsky EB;Kaul V;Paschall J;Church DM;Bunke B;Kunig D;Moreno-De-Luca D;Moreno-De-Luca A;Mulle JG;Warren ST;Richard G;Compton JG;Fuller AE;Gliem TJ;Huang S;Collinson MN;Beal SJ;Ackley T;Pickering DL;Golden DM;Aston E;Whitby H;Shetty S;Rossi MR;Rudd MK;South ST;Brothman AR;Sanger WG;Iyer RK;Crolla JA;Thorland EC;Aradhya S;Ledbetter DH;Martin CL
通讯作者：
Martin CL