Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis
Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis
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DOI：
10.1073/pnas.1902041116
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发表时间：
2019-07-23
影响因子：
11.1
通讯作者：
Lifton, Richard P.
中科院分区：
文献类型：
--
作者：
Timberlake, Andrew T.;Jin, Sheng Chih;Lifton, Richard P.
颅缝早闭是一种常见的先天性畸形，其特征是颅顶的一条或多条缝过早融合。综合征病例，具有额外的先天性异常，占CS的15%。虽然许多基因的综合征CS已被确定，许多综合征病例的原因仍然未知。我们对12例综合征型CS病例及其父母进行了外显子组测序，这些患者先前的遗传评估未显示。在8个对LOF突变高度不耐受的基因中发现了损伤性从头突变或传递性功能丧失（LOF）突变（P = 4.0 x 10（-8））;此外，在SOX 11中发现了一种罕见的损伤性突变，其不耐受水平较低。四个先证者在TFAP 2B中有罕见的破坏性突变（2个从头），TFAP 2B是一种协调神经嵴细胞迁移和分化的转录因子;这种突变负担非常显著（P = 8.2 x 10（-12））。三个先证者在GLI 2、SOX 11或GPC 4中具有罕见的破坏性突变，这些突变在Hedgehog、BMP和Wnt信号通路中起作用;这些通路中的其他基因先前与综合征CS有关。类似地，在编码染色质修饰剂KAT 6A和编码连环蛋白α-1的CTNNA 1的基因中鉴定出破坏性的从头突变。这些发现确立了TFAP 26作为CS基因，对评估这些家庭中后续儿童的风险具有意义，并提供了证据表明其他基因与综合征CS有关。这种高产率表明，当已知疾病基因座的测序未揭示时，对综合征CS患者进行外显子组测序的价值。
Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (P = 4.0 x 10(-8)); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 x 10(-12)). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A, and CTNNA1, encoding catenin alpha-1. These findings establish TFAP26 as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.