Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH.
Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH.
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DOI：
10.1002/ajmg.a.33618
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发表时间：
2010-10
影响因子：
2
通讯作者：
Pober, Barbara R.
中科院分区：
文献类型：
--
作者：
Kantarci, Sibel;Ackerman, Kate G.;Russell, Meaghan K.;Longoni, Mauro;Sougnez, Carrie;Noonan, Kristin M.;Hatchwell, Eli;Zhang, Xiaoyun;Pieretti-Vanmarcke, Rafael;Anyane-Yeboa, Kwame;Dickman, Paul;Wilson, Jay;Donahoe, Patricia K.;Pober, Barbara R.
关键词：
细胞遗传学和分子细胞遗传学研究表明先天性膈疝（CDH）与染色体14q41q42缺失有关。在这项研究中，我们通过多重连接依赖探针扩增（multiplex lig- dependent probe amplification， MLPA）技术筛选了一个大型CDH队列（N=179）在这段时间内的微缺失，并对其中的两个候选基因——分派1 （DISP1）和智人h2.0样同源盒（HLX）进行了测序。MLPA分析证实了两个病例中该区域的缺失，一个未报道的46，XY,del(1)（q41q42.13）核型患者和一个先前报道的Fryns综合征表型患者。HLX测序在一名分离CDH患者中显示了一种新的母系遗传单核苷酸变异（c.27C>G），而DISP1测序在一名左侧Bochdalek疝合并多种其他异常的男性中显示了一种新的嵌合替换（c.4412C>G; p.Ala1471Gly）。焦磷酸测序显示，突变等位基因分别存在于43%、12%和4.5%的患者淋巴母细胞样细胞、外周血淋巴细胞和唾液细胞中。我们在小鼠横膈膜形成的第E11.5天检测了Disp1的表达，并证实它存在于胸膜襞以及附近的肺中，后者也表达Sonic hedgehog （Shh）。我们的报告描述了一例复杂CDH患者的首次新发DISP1点突变。将这一发现与Disp1胚胎小鼠膈肌和肺组织表达以及先前报道的CDH患者的人类染色体14q41q42畸变相结合，表明Disp1可能值得进一步考虑作为CDH候选基因。
Cytogenetic and molecular cytogenetic studies demonstrate association between congenital diaphragmatic hernia (CDH) and chromosome 1q41q42 deletions. In this study, we screened a large CDH cohort (N=179) for microdeletions in this interval by the multiplex ligation-dependent probe amplification (MLPA) technique, and also sequenced two candidate genes located therein, dispatched 1 (DISP1) and homo sapiens H2.0-like homeobox (HLX). MLPA analysis verified deletions of this region in two cases, an unreported patient with a 46,XY,del(1)(q41q42.13) karyotype and a previously reported patient with a Fryns syndrome phenotype. HLX sequencing showed a novel but maternally inherited single nucleotide variant (c.27C>G) in a patient with isolated CDH, while DISP1 sequencing revealed a mosaic de novo heterozygous substitution (c.4412C>G; p.Ala1471Gly) in a male with a left-sided Bochdalek hernia plus multiple other anomalies. Pyrosequencing demonstrated the mutant allele was present in 43%, 12%, and 4.5% of the patient’s lymphoblastoid, peripheral blood lymphocytes, and saliva cells, respectively. We examined Disp1 expression at day E11.5 of mouse diaphragm formation and confirmed its presence in the pleuroperitoneal fold, as well as the nearby lung which also expresses Sonic hedgehog (Shh). Our report describes the first de novo DISP1 point mutation in a patient with complex CDH. Combining this finding with Disp1 embryonic mouse diaphragm and lung tissue expression, as well as previously reported human chromosome 1q41q42 aberrations in patients with CDH, suggests that DISP1 may warrant further consideration as a CDH candidate gene.
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