Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway
Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway
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DOI：
10.1016/j.ajhg.2018.12.010
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发表时间：
2019-02-07
影响因子：
9.8
通讯作者：
Stankiewicz, Pawe
中科院分区：
文献类型：
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作者：
Karolak, Justyna A.;Vincent, Marie;Stankiewicz, Pawe
肺分支形态发生的原发性缺陷导致新生儿致命性肺发育不全，目前尚不完全清楚。为了阐明人类肺发育的病理机制，我们研究了一组独特的样本，这些样本来自临床和组织病理学诊断为间质性新生儿肺疾病的死者：腺泡发育不良（n = 14）、先天性肺泡发育不良（n = 2）和其他致死性肺发育不良（n = 10）。我们在16/26（61%）个体中发现了涉及TBX4 （n = 8和n = 2）或FGF10 （n = 2和n = 2）的罕见杂合拷贝数变异缺失或单核苷酸变异（SNVs）。除TBX4外，在7例肺发育不全患者中发现的17q23.1q23.2位点类似于2mb复发性和非复发性缺失的重叠也删除了一个肺特异性增强子区域。编码变异涉及TBX4或FGF10的个体在预测的肺特异性增强子区域中也至少有一个非编码SNV，而在13个具有重叠缺失但没有任何结构性肺异常的对照个体中则没有。涉及TBX4或FGF10的罕见编码变异与假定的亚形态非编码snv的发生表明这些肺发育不全存在复杂的复合遗传。此外，它们支持TBX4-FGF10-FGFR2上皮-间质信号在人肺器官发生中的重要性，并有助于解释在这些罕见的致死性肺发育障碍中观察到的组织病理学连续性。
Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping similar to 2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.