High prevalence of deleterious mutations in concomitant nonsyndromic cleft and outflow tract heart defects.
High prevalence of deleterious mutations in concomitant nonsyndromic cleft and outflow tract heart defects.
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伴随的非综合征性心脏裂隙和流出道心脏缺陷中有害基因突变的高发。
DOI：
10.1002/ajmg.a.62748
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发表时间：
2022-07
影响因子：
2
通讯作者：
Kumar, Subramanyan Ram
中科院分区：
文献类型：
--
作者：
Munabi, Naikhoba C. O.;Mikhail, Shady;Toubat, Omar;Webb, Michelle;Auslander, Allyn;Sanchez-Lara, Pedro A.;Manojlovic, Zarko;Schmidt, Ryan J.;Craig, David;Magee, William P.;Kumar, Subramanyan Ram
我们以前的工作表明，丰富的流出道（OFT）先天性心脏病（CHD）的儿童唇腭裂（CL/P）提示在共同的潜在发展途径的紊乱。目前的初步研究探讨了伴随非综合征CL/P和OFT CHD表型的潜在遗传学。在洛杉矶儿童医院接受CL/P手术的575名患者中，7名患有OFT CHD、染色体微阵列分析阴性且无可识别的综合征相关性的患者与其父母一起招募（如可用）。对先证者进行了血液样本的全基因组测序和基于全血的RNA测序。在6/7（85.7%）的先证者中鉴定出致病性或潜在致病性变异。共突变了7个候选基因（CHD 7、SMARCA 4、MED 12、APOB、RNF 213、SETX和JAG 1）。变体的基因本体分析预测参与结合（100%）、转录调节（42.9%）和解旋酶活性（42.9%）。4名患者（57.1%）表达了先前参与Wnt信号通路的基因变体（CHD 7、SMARCA 4、MED 12和RNF 213）。我们对CL/P和OFT合并CHD表型的一小群患者进行的初步分析表明，有害突变的患病率可能很高。在我们的队列中，发现与Wnt信号相关的分子突变的过度表达。这些变异可能代表已知单基因疾病基因中扩大的表型异质性，或提供共享发育途径的新证据。这些突变和随后的发育紊乱导致CL/P和OFT CHD表型的机制影响需要在更大的患者队列中进一步分析。
Our previous work demonstrating enrichment of outflow tract (OFT) congenital heart disease (CHD) in children with cleft lip and/or palate (CL/P) suggests derangements in common underlying developmental pathways. The current pilot study examines the underlying genetics of concomitant nonsyndromic CL/P and OFT CHD phenotype. Of 575 patients who underwent CL/P surgery at Children's Hospital Los Angeles, seven with OFT CHD, negative chromosomal microarray analysis, and no recognizable syndromic association were recruited with their parents (as available). Whole genome sequencing of blood samples paired with whole‐blood‐based RNA sequencing for probands was performed. A pathogenic or potentially pathogenic variant was identified in 6/7 (85.7%) probands. A total of seven candidate genes were mutated (CHD7, SMARCA4, MED12, APOB, RNF213, SETX, and JAG1). Gene ontology analysis of variants predicted involvement in binding (100%), regulation of transcription (42.9%), and helicase activity (42.9%). Four patients (57.1%) expressed gene variants (CHD7, SMARCA4, MED12, and RNF213) previously involved in the Wnt signaling pathway. Our pilot analysis of a small cohort of patients with combined CL/P and OFT CHD phenotype suggests a potentially significant prevalence of deleterious mutations. In our cohort, an overrepresentation of mutations in molecules associated with Wnt‐signaling was found. These variants may represent an expanded phenotypic heterogeneity within known monogenic disease genes or provide novel evidence of shared developmental pathways. The mechanistic implications of these mutations and subsequent developmental derangements resulting in the CL/P and OFT CHD phenotype require further analysis in a larger cohort of patients.
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影响因子：
9.6
作者：
Chang, Sung-A;Song, Ju Sun;Kim, Duk-Kyung
通讯作者：
Kim, Duk-Kyung
影响因子：
2.5
作者：
Casey, Liam M.;Lan, Yu;Jiang, Rulang
通讯作者：
Jiang, Rulang
DOI：
10.1073/pnas.1013751108
发表时间：
2011-02-08
影响因子：
11.1
作者：
Griffin, Courtney T.;Curtis, Carol D.;Magnuson, Terry
通讯作者：
Magnuson, Terry
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.15585/mmwr.mm6602a1
发表时间：
2017-01-20
期刊：
MMWR. Morbidity and mortality weekly report
影响因子：
--
作者：
Arth AC;Tinker SC;Simeone RM;Ailes EC;Cragan JD;Grosse SD
通讯作者：
Grosse SD