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.

中文翻译：

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伴有复杂颅脑前突的儿童中SMAD6和TCF12的移码突变同时出现。

非综合征性颅脑前突症（CS）影响2350例活产中的1例。最近的研究表明，很大一部分病例是由从头或罕见的传播突变引起的，这些突变促进颅骨缝线过早地分化为成骨细胞。患有非综合征性矢状和冠状CS的患者中，SMAD6和TCF12中罕见的杂合功能丧失（LOF）突变高度丰富。有趣的是，这两个突变都显示出惊人的不完全外显率，暗示着修饰等位基因的作用。就SMAD6而言，是BMP2附近的常见变体大大增加了矢状CS的渗透率。在这里，我们报道了在首次手术后两个月内先天性矢状和冠状颅前突合并CS复发的先证者，要求第二次手术以在六个月大时重新建立缝合通畅性。外显子测序揭示了一种罕见的透射移码突变SMAD6（第152个FS * 27）从一个未受影响的父，不存在共同的遗传BMP2风险的变体，并且在从头移码突变TCF12（p.E548fs * 14）。SMAD6和TCF12独立地抑制BMP信号转导的转录目标。这些发现与这些突变的上位性，在该先证者中CS的渗透率和严重性增加是一致的。他们还将两个孟德尔突变产生的复合表型添加到列表中，并支持在非典型CS病例中使用外显子组测序。