Genetic Analysis and Functional Assessment of a TGFBR2 Variant in Micrognathia and Cleft Palate.
Genetic Analysis and Functional Assessment of a TGFBR2 Variant in Micrognathia and Cleft Palate.
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小颌畸形和腭裂中 TGFBR2 变异体的遗传分析和功能评估。
DOI：
10.1101/2024.04.08.588524
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Stottmann,RolfW
中科院分区：
文献类型：
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作者：
Michaels,Jes-Rite;Husami,Ammar;Vontell,AndrewM;Brugmann,SamanthaA;Stottmann,RolfW
唇裂和腭裂是最常见的先天性畸形之一，分别是胚胎颅面突或腭架不完全融合的结果。我们知道遗传学在这些异常中起着很大的作用，但已知的致病基因清单还远远不够。作为小颌畸形和腭裂患者更大测序工作的一部分，我们确定了转化生长因子β受体2（TGFBR 2）的候选变体，该变体非常罕见，改变了高度保守的氨基酸，并通过许多指标预测为致病性。家族史和群体遗传学表明，这种特殊的变异将是不完全的外显，但这种基因已令人信服地牵连在颅面发育。为了验证这可能是一个因果变异的假设，我们使用基因组编辑在一个新的小鼠模型中创建了正向变异。令人惊讶的是，Tgfbr 2 V387 M小鼠没有表现出颅面异常或存活率降低，这表明这实际上不是腭裂/小颌畸形的因果变异。计算机预测和小鼠表型之间的差异突出了将人类遗传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未来的变异TGFBR 2正在进行测序的先天性颅面畸形患者。
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.