Poot Martin
Department of Human Genetics, University of Würzburg, Würzburg, Germany.
Mol Syndromol. 2019 Feb;10(1-2):24-39. doi: 10.1159/000490480. Epub 2018 Jul 7.
Craniosynostosis refers to a condition during early development in which one or more of the fibrous sutures of the skull prematurely fuse by turning into bone, which produces recognizable patterns of cranial shape malformations depending on which suture(s) are affected. In addition to cases with isolated cranial dysmorphologies, craniosynostosis appears in syndromes that include skeletal features of the eyes, nose, palate, hands, and feet as well as impairment of vision, hearing, and intellectual development. Approximately 85% of the cases are nonsyndromic sporadic and emerge after de novo structural genome rearrangements or single nucleotide variation, while the remainders consist of syndromic cases following mendelian inheritance. By karyotyping, genome wide linkage, and CNV analyses as well as by whole exome and whole genome sequencing, numerous candidate genes for craniosynostosis belonging to the FGF, Wnt, BMP, Ras/ERK, ephrin, hedgehog, STAT, and retinoic acid signaling pathways have been identified. Many of the craniosynostosis-related candidate genes form a functional network based upon protein-protein or protein-DNA interactions. Depending on which node of this craniosynostosis-related network is affected by a gene mutation or a change in gene expression pattern, a distinct craniosynostosis syndrome or set of phenotypes ensues. Structural variations may alter the dosage of one or several genes or disrupt the genomic architecture of genes and their regulatory elements within topologically associated chromatin domains. These may exert dominant effects by either haploinsufficiency, dominant negative partial loss of function, gain of function, epistatic interaction, or alteration of levels and patterns of gene expression during development. Molecular mechanisms of dominant modes of action of these mutations may include loss of one or several binding sites for cognate protein partners or transcription factor binding sequences. Such losses affect interactions within functional networks governing development and consequently result in phenotypes such as craniosynostosis. Many of the novel variants identified by genome wide CNV analyses, whole exome and whole genome sequencing are incorporated in recently developed diagnostic algorithms for craniosynostosis.
颅缝早闭是指在早期发育过程中，颅骨的一条或多条纤维性骨缝过早地融合成骨，根据受影响的骨缝不同，会产生可识别的颅骨形状畸形模式。除了孤立性颅骨畸形的病例外，颅缝早闭还出现在一些综合征中，这些综合征包括眼睛、鼻子、腭、手和脚的骨骼特征，以及视力、听力和智力发育受损。大约85%的病例是非综合征性散发性的，在新发结构基因组重排或单核苷酸变异后出现，其余病例则是遵循孟德尔遗传的综合征性病例。通过核型分析、全基因组连锁分析和拷贝数变异（CNV）分析，以及全外显子组和全基因组测序，已经确定了许多与颅缝早闭相关的候选基因，它们属于成纤维细胞生长因子（FGF）、Wnt、骨形态发生蛋白（BMP）、Ras/细胞外信号调节激酶（ERK）、 Ephrin、刺猬蛋白、信号转导和转录激活因子（STAT）以及视黄酸信号通路。许多与颅缝早闭相关的候选基因基于蛋白质-蛋白质或蛋白质-DNA相互作用形成一个功能网络。根据该颅缝早闭相关网络的哪个节点受到基因突变或基因表达模式变化的影响，会产生不同的颅缝早闭综合征或一组表型。结构变异可能会改变一个或几个基因的剂量，或破坏基因及其在拓扑相关染色质结构域内的调控元件的基因组结构。这些变异可能通过单倍体不足、显性负性部分功能丧失、功能获得、上位性相互作用或发育过程中基因表达水平和模式的改变发挥显性作用。这些突变的显性作用模式的分子机制可能包括失去一个或几个同源蛋白质伙伴的结合位点或转录因子结合序列。这种缺失会影响控制发育的功能网络内的相互作用，从而导致诸如颅缝早闭等表型。通过全基因组CNV分析、全外显子组和全基因组测序鉴定出的许多新变异已被纳入最近开发的颅缝早闭诊断算法中。
