PDF(Pubmed)
Abstract：
Cleft lip and cleft palate are among the most common congenital anomalies and are the result of incomplete fusion of embryonic craniofacial processes or palatal shelves, respectively. We know that genetics play a large role in these anomalies but the list of known causal genes is far from complete. As part of a larger sequencing effort of patients with micrognathia and cleft palate we identified a candidate variant in transforming growth factor beta receptor 2 (TGFBR2) which is rare, changing a highly conserved amino acid, and predicted to be pathogenic by a number of metrics. The family history and population genetics would suggest this specific variant would be incompletely penetrant, but this gene has been convincingly implicated in craniofacial development. In order to test the hypothesis this might be a causal variant, we used genome editing to create the orthologous variant in a new mouse model. Surprisingly, Tgfbr2V387M mice did not exhibit craniofacial anomalies or have reduced survival suggesting this is, in fact, not a causal variant for cleft palate/ micrognathia. The discrepancy between in silico predictions and mouse phenotypes highlights the complexity of translating human genetic findings to mouse models. We expect these findings will aid in interpretation of future variants seen in TGFBR2 from ongoing sequencing of patients with congenital craniofacial anomalies.
摘要：
唇裂和腭裂是最常见的先天性异常，是胚胎颅面突或腭架不完全融合的结果。分别。我们知道遗传学在这些异常中起着重要作用，但已知的因果基因列表远未完成。作为小颌畸形和腭裂患者的更大测序工作的一部分，我们确定了一种罕见的转化生长因子β受体2（TGFBR2）的候选变体，改变一个高度保守的氨基酸，并通过许多指标预测为致病性。家族史和人口遗传学表明，这种特定的变异将是不完全渗透的，但是这个基因与颅面发育有关.为了检验假设，这可能是一个因果变体，我们使用基因组编辑在新的小鼠模型中创建直系同源变体.令人惊讶的是,Tgfbr2V387M小鼠没有表现出颅面异常或存活率降低，这表明这是，事实上,不是腭裂/小颌畸形的因果变异。计算机模拟预测与小鼠表型之间的差异凸显了将人类基因发现转化为小鼠模型的复杂性。我们希望这些发现将有助于解释先天性颅面异常患者正在进行的测序中在TGFBR2中看到的未来变异。
