A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia.
A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia.
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DOI：
10.1002/ajmg.a.35664
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发表时间：
2012-12
影响因子：
2
通讯作者：
Brunelli, Luca
中科院分区：
文献类型：
--
作者：
Arrington, Cammon B.;Bleyl, Steven B.;Matsunami, Nori;Bowles, Neil E.;Leppert, Tami I.;Demarest, Bradley L.;Osborne, Karen;Yoder, Bradley A.;Byrne, Janice L.;Schiffman, Joshua D.;Null, Donald M.;DiGeronimo, Robert;Rollins, Michael;Faix, Roger;Comstock, Jessica;Camp, Nicola J.;Leppert, Mark F.;Yost, H. Joseph;Brunelli, Luca
先天性膈疝（CDH）是一种导致新生儿死亡率高的膈肌发育缺陷。孤立性或非综合征性CDH被认为是一种多因素疾病，有强有力的证据表明与遗传因素有关。由于孤立性CDH的遗传性较低，因此基于家族的遗传学方法尚未确定与该缺陷相关的遗传因素。利用犹他州人口数据库，我们从几个孤立性CDH发病率高的大家庭中确定了远亲患者。使用高密度基因分型，7例患者进行了分析纯合性排除罕见等位基因定位（HERAM）和分阶段单倍型共享（HapShare），我们开发的两种方法来映射共享的染色体区域。我们的患者队列共有三个先前与CDH无关的区域，即2q11.2-q12.1，4p 13和7q11.2，以及两个先前与CDH相关的区域，即8p23.1和15q26.2。后一个区域包含GATA 4和NR 2F 2，这两个基因与小鼠膈肌形成有关。有趣的是，三名患者共享8p23.1位点，其中一人还携带15q26.2片段。在GATA 4和NR 2F 2中没有发现编码变异，但在GATA 4的内含子1中发现了一种罕见的共享变异。这项工作显示了遗传性在孤立性CDH中的作用。我们基于家族的策略揭示了可能与疾病相关的新的染色体区域，并表明GATA 4和NR 2F 2的非编码变体可能有助于孤立性CDH的发展。这种方法可以加速发现导致多因素疾病（例如孤立性CDH）的基因和调节元件。
Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, i.e. 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, i.e. 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.
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影响因子：
3.7
作者：
Jiang H;Orr A;Guernsey DL;Robitaille J;Asselin G;Samuels ME;Dubé MP
通讯作者：
Dubé MP
影响因子：
64.5
作者：
KREIDBERG, JA;SARIOLA, H;JAENISCH, R
通讯作者：
JAENISCH, R
DOI：
10.1002/ajmg.1320210115
发表时间：
1985-01-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
CZEIZEL, A;KOVACS, M
通讯作者：
KOVACS, M
影响因子：
1.9
作者：
Arrington CB;Dowse BR;Bleyl SB;Bowles NE
通讯作者：
Bowles NE
DOI：
10.1002/ajmg.c.30128
发表时间：
2007-05-15
影响因子：
3.1
作者：
Ackerman, Kate G.;Greer, John J.
通讯作者：
Greer, John J.