Ye Xiaoqian, Guilmatre Audrey, Reva Boris, Peter Inga, Heuzé Yann, Richtsmeier Joan T, Fox Deborah J, Goedken Rhinda J, Jabs Ethylin Wang, Romitti Paul A
New York and Albany, N.Y.; University Park, Pa.; Iowa City, Iowa; Wuhan, People's Republic of China; and Paris and Pessac, France From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai; the Congenital Malformations Registry, New York State Department of Health; the Department of Anthropology, Pennsylvania State University; the Department of Epidemiology, University of Iowa; the State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University; the Department of Pediatric Hematology, Robert Debré Hospital; and Université de Bordeaux, UMR5199 PACEA, Bordeaux Archaeological Sciences Cluster of Excellence.
Plast Reconstr Surg. 2016 Mar;137(3):952-961. doi: 10.1097/01.prs.0000479978.75545.ee.
Craniosynostosis is a condition that includes the premature fusion of one or multiple cranial sutures. Among various craniosynostosis forms, sagittal nonsyndromic craniosynostosis is the most prevalent. Although different gene mutations have been identified in some craniosynostosis syndromes, the cause of sagittal nonsyndromic craniosynostosis remains largely unknown.
To screen for candidate genes for sagittal nonsyndromic craniosynostosis, the authors sequenced DNA of 93 sagittal nonsyndromic craniosynostosis patients from a population-based study conducted in Iowa and New York states. FGFR1-3 mutational hotspots and the entire TWIST1, RAB23, and BMP2 coding regions were screened because of their known roles in human nonsyndromic or syndromic sagittal craniosynostosis, expression patterns, and/or animal model studies.
The authors identified two rare variants in their cohort. A FGFR1 insertion c.730_731insG, which led to a premature stop codon, was predicted to abolish the entire immunoglobulin-like III domain, including the ligand-binding region. A c.439C>G variant was observed in TWIST1 at its highly conserved loop domain in another patient. The patient's mother harbored the same variant and was reported with jaw abnormalities. These two variants were not detected in 116 alleles from unaffected controls or seen in the several databases; however, TWIST1 variant was found in a low frequency of 0.000831 percent in Exome Aggregation Consortium database.
The low mutation detection rate indicates that these genes account for only a small proportion of sagittal nonsyndromic craniosynostosis patients. The authors' results add to the perception that sagittal nonsyndromic craniosynostosis is a complex developmental defect with considerable genetic heterogeneity.
CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.
颅缝早闭是一种包括一条或多条颅缝过早融合的病症。在各种颅缝早闭形式中，矢状缝非综合征性颅缝早闭最为常见。尽管在一些颅缝早闭综合征中已鉴定出不同的基因突变，但矢状缝非综合征性颅缝早闭的病因在很大程度上仍不清楚。
为了筛选矢状缝非综合征性颅缝早闭的候选基因，作者对来自爱荷华州和纽约州一项基于人群的研究中的93例矢状缝非综合征性颅缝早闭患者的DNA进行了测序。由于FGFR1 - 3突变热点以及整个TWIST1、RAB23和BMP2编码区域在人类非综合征性或综合征性矢状缝颅缝早闭中的已知作用、表达模式和/或动物模型研究，对其进行了筛选。
作者在其队列中鉴定出两个罕见变异。一个FGFR1插入突变c.730_731insG，导致提前终止密码子，预计会消除整个免疫球蛋白样III结构域，包括配体结合区域。在另一名患者的TWIST1高度保守的环结构域中观察到一个c.439C>G变异。该患者的母亲携带相同变异，并报告有颌骨异常。在116个未受影响对照的等位基因中未检测到这两个变异，在几个数据库中也未见到；然而，在外显子聚合联盟数据库中发现TWIST1变异的频率较低，为0.000831%。
低突变检测率表明这些基因仅占矢状缝非综合征性颅缝早闭患者的一小部分。作者的结果进一步支持了矢状缝非综合征性颅缝早闭是一种具有相当大遗传异质性的复杂发育缺陷的观点。
临床问题/证据水平：风险，II。
