PDF(Pubmed)
Abstract：
OBJECTIVE: Occurring once in every 2000 live births, craniosynostosis (CS) is the most frequent cranial birth defect. Although the genetic etiologies of syndromic CS cases are well defined, the genetic cause of most nonsyndromic cases remains unknown.
METHODS: The authors analyzed exome or RNA sequencing data from 876 children with nonsyndromic CS, including 291 case-parent trios and 585 additional probands. The authors also utilized the GeneMatcher platform and the Gabriella Miller Kids First genome sequencing project to identify additional CS patients with AXIN1 mutations.
RESULTS: The authors describe 11 patients with nonsyndromic CS harboring rare, damaging mutations in AXIN1, an inhibitor of Wnt signaling. AXIN1 regulates signaling upstream of key mediators of osteoblast differentiation. Three of the 6 mutations identified in trios occurred de novo in the proband, while 3 were transmitted from unaffected parents. Patients with nonsyndromic CS were highly enriched for mutations in AXIN1 compared to both expectation (p = 0.0008) and exome sequencing data from > 76,000 healthy controls (p = 2.3 × 10-6), surpassing the thresholds for genome-wide significance.
CONCLUSIONS: These findings describe the first phenotype associated with mutations in AXIN1, with mutations identified in approximately 1% of nonsyndromic CS cases. The results strengthen the existing link between Wnt signaling and maintenance of cranial suture patency and have implications for genetic testing in families with CS.
METHODS: The authors analyzed exome or RNA sequencing data from 876 children with nonsyndromic CS, including 291 case-parent trios and 585 additional probands. The authors also utilized the GeneMatcher platform and the Gabriella Miller Kids First genome sequencing project to identify additional CS patients with AXIN1 mutations.
RESULTS: The authors describe 11 patients with nonsyndromic CS harboring rare, damaging mutations in AXIN1, an inhibitor of Wnt signaling. AXIN1 regulates signaling upstream of key mediators of osteoblast differentiation. Three of the 6 mutations identified in trios occurred de novo in the proband, while 3 were transmitted from unaffected parents. Patients with nonsyndromic CS were highly enriched for mutations in AXIN1 compared to both expectation (p = 0.0008) and exome sequencing data from > 76,000 healthy controls (p = 2.3 × 10-6), surpassing the thresholds for genome-wide significance.
CONCLUSIONS: These findings describe the first phenotype associated with mutations in AXIN1, with mutations identified in approximately 1% of nonsyndromic CS cases. The results strengthen the existing link between Wnt signaling and maintenance of cranial suture patency and have implications for genetic testing in families with CS.
摘要：
目标：每2000名活产儿发生一次，颅骨融合（CS）是最常见的颅骨出生缺陷。虽然综合征性CS病例的遗传病因是明确的，大多数非综合征病例的遗传原因尚不清楚.
方法：作者分析了876名非综合征性CS患儿的外显子组或RNA测序数据，包括291个案例家长三重奏和585个额外的先证者。作者还利用GeneMatcher平台和GabriellaMillerKidsFirst基因组测序项目来鉴定具有AXIN1突变的其他CS患者。
结果：作者描述了11例非综合征性CS患者，AXIN1，Wnt信号的抑制剂的破坏性突变。AXIN1调节成骨细胞分化的关键介质的上游信号传导。在三重奏中鉴定的6个突变中有3个在先证中从头发生，而3则是从未受影响的父母那里传播的。与预期（p=0.0008）和来自>76,000名健康对照（p=2.3×10-6）的外显子组测序数据相比，非综合征性CS患者的AXIN1突变高度富集。超过了全基因组意义的阈值。
结论：这些发现描述了与AXIN1突变相关的第一个表型，在约1%的非综合征性CS病例中发现了突变。结果加强了Wnt信号传导与维持颅骨缝合通畅之间的现有联系，并对CS家庭的基因检测具有意义。
方法：作者分析了876名非综合征性CS患儿的外显子组或RNA测序数据，包括291个案例家长三重奏和585个额外的先证者。作者还利用GeneMatcher平台和GabriellaMillerKidsFirst基因组测序项目来鉴定具有AXIN1突变的其他CS患者。
结果：作者描述了11例非综合征性CS患者，AXIN1，Wnt信号的抑制剂的破坏性突变。AXIN1调节成骨细胞分化的关键介质的上游信号传导。在三重奏中鉴定的6个突变中有3个在先证中从头发生，而3则是从未受影响的父母那里传播的。与预期（p=0.0008）和来自>76,000名健康对照（p=2.3×10-6）的外显子组测序数据相比，非综合征性CS患者的AXIN1突变高度富集。超过了全基因组意义的阈值。
结论：这些发现描述了与AXIN1突变相关的第一个表型，在约1%的非综合征性CS病例中发现了突变。结果加强了Wnt信号传导与维持颅骨缝合通畅之间的现有联系，并对CS家庭的基因检测具有意义。
