Congenital diaphragmatic hernia (CDH) etiology as revealed by pathway genetics
Congenital diaphragmatic hernia (CDH) etiology as revealed by pathway genetics
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DOI：
10.1002/ajmg.c.30132
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发表时间：
2007-05-15
影响因子：
3.1
通讯作者：
Donahoe, Patricia K.
中科院分区：
文献类型：
--
作者：
Kantarci, Sibel;Donahoe, Patricia K.
先天性腹股沟疝是一种常见的出生缺陷，具有较高的发病率和死亡率。270例CDH患者被确定，仔细分型，并分类为孤立（单独的隔膜缺陷）或复杂（有其他异常）的情况下。我们建立了不同的策略来揭示人类CDH关键染色体基因座和基因。用于测序分析的候选基因选自CDH动物模型、人类复发性染色体畸变的遗传间隔（如15q26.1-q26.2或1 q41-q42.12）以及维甲酸和相关途径中的基因和已知参与胚胎肺发育的基因。例如，FOG 2、GATA 4和COUP-TFII都是正常横膈膜和肺发育所需的，并且可能都处于相同的遗传和分子途径中。首先在一个大的近交系，然后在四个多发性家系与唐-巴综合征（DBS）与CDH的连锁分析。10 K SNP芯片和微卫星标记显示DBS位点位于染色体2q23.3-q31.1。我们应用基于阵列的比较基因组杂交（aCGH）技术，以超过30个，大多数是复杂的，CDH患者，并发现了一个从头微缺失的患者与Fryns综合征相关的CDH。荧光原位杂交（FISH）和多重连接依赖性探针扩增（MLPA）技术使我们能够进一步确定缺失间隔。我们的目标是确定遗传间隔，并在这些基因中，优先考虑可能揭示分子途径的基因，其中任何一步的突变可能导致相同的表型。更重要的是，阐明的途径可能最终提供线索的治疗策略。(C)2007 Wiley-Liss，Inc.
Congenital diaphragmatic hernia (CDH) is a common birth defect with high mortality and morbidity. Two hundred seventy CDH patients were ascertained, carefully phenotyped, and classified as isolated (diaphragm defects alone) or complex (with additional anomalies) cases. We established different strategies to reveal CDH-critical chromosome loci and genes in humans. Candidate genes for sequencing analyses were selected from CDH animal models, genetic intervals of recurrent chromosomal aberration in humans, such as 15q26.1-q26.2 or 1q41-q42.12, as well as genes in the retinoic acid and related pathways and those known to be involved in embryonic lung development. For instance, FOG2, GATA4, and COUP-TFII are all needed for both normal diaphragm and lung development and are likely all in the same genetic and molecular pathway. Linkage analysis was applied first in a large inbred family and then in four multiplex families with Donnai-Barrow syndrome (DBS) associated with CDH. 10K SNP chip and microsatellite markers revealed a DBS locus on chromosome 2q23.3-q31.1. We applied array-based comparative genomic hybridization (aCGH) techniques to over 30, mostly complex, CDH patients and found a de novo microdeletion in a patient with Fryns syndrome related to CDH. Fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) techniques allowed us to further define the deletion interval. Our aim is to identify genetic intervals and, in those, to prioritize genes that might reveal molecular pathways, mutations in any step of which, might contribute to the same phenotype. More important, the elucidation of pathways may ultimately provide clues to treatment strategies. (C) 2007 Wiley-Liss, Inc.