Co-occurrence of frameshift mutations in SMAD6 and TCF12 in a child with complex craniosynostosis.
Co-occurrence of frameshift mutations in SMAD6 and TCF12 in a child with complex craniosynostosis.
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DOI：
10.1038/s41439-018-0014-x
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发表时间：
2018
影响因子：
1.5
通讯作者：
Lifton RP
中科院分区：
文献类型：
--
作者：
Timberlake AT;Wu R;Nelson-Williams C;Furey CG;Hildebrand KI;Elton SW;Wood JS;Persing JA;Lifton RP
非综合征性颅缝早闭 (CS) 影响 2,350 名活产儿中就有 1 人患有非综合征性颅缝早闭 (CS)。最近的研究表明，很大一部分病例是由新的或罕见的传播突变引起的，这些突变会促进颅缝中成骨细胞的过早分化。 SMAD6 和 TCF12 的罕见杂合功能丧失 (LOF) 突变分别在非综合征矢状面和冠状面 CS 患者中高度富集。有趣的是，这两种突变都显示出惊人的不完全外显率，表明修饰等位基因的作用。就 SMAD6 而言，BMP2 附近的常见变异极大地增加了矢状 CS 的外显率。在这里，我们报告了一名先证者，同时患有矢状位和冠状位颅缝早闭，并且在初次手术后两个月内出现了极不寻常的 CS 复发，需要在六个月时进行第二次手术以重新建立缝线通畅。外显子组测序揭示了 SMAD6 中罕见的遗传性移码突变 (p. 152 fs*27)，遗传自未受影响的父母，不存在常见的 BMP2 风险变异，TCF12 中存在从头移码突变 (p.E548fs*14)。 SMAD6 和 TCF12 独立抑制 BMP 信号转导的转录靶标。这些发现与这些突变的上位性一致，增加了该先证者 CS 的外显率和严重程度。他们还添加了由两种孟德尔突变产生的复合表型列表，并支持外显子组测序在非典型 CS 病例中的实用性。
Non-syndromic craniosynostosis (CS) affects 1 in 2350 live births. Recent studies have shown that a significant fraction of cases are caused by de novo or rare transmitted mutations that promote premature osteoblast differentiation in cranial sutures. Rare heterozygous loss-of-function (LOF) mutations in SMAD6 and TCF12 are highly enriched in patients with non-syndromic sagittal and coronal CS, respectively. Interestingly, both mutations show striking incomplete penetrance, suggesting a role for modifying alleles; in the case of SMAD6, a common variant near BMP2 drastically increases penetrance of sagittal CS. Here, we report a proband presenting with both sagittal and coronal craniosynostosis with the highly unusual recurrence of CS within two months of initial surgery, requiring a second operation to re-establish suture patency at six months of age. Exome sequencing revealed a rare transmitted frameshift mutation in SMAD6 (p. 152 fs*27) inherited from an unaffected parent, absence of the common BMP2 risk variant, and a de novo frameshift mutation in TCF12 (p.E548fs*14). SMAD6 and TCF12 independently inhibit transcriptional targets of BMP signaling. The findings are consistent with epistasis of these mutations, increasing penetrance and severity of CS in this proband. They also add to the list of composite phenotypes resulting from two Mendelian mutations, and support the utility of exome sequencing in atypical CS cases.