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.

中文翻译：

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与颅骨前突相关的结构基因组变异。

颅骨吻合术是指早期发育中的一种情况，其中头骨的一根或多根纤维缝合线过早地融合成骨，从而融合在一起，这会根据可缝合的缝合线产生可识别的颅骨形状畸变模式。除颅骨畸形孤立的病例外，颅骨融合症还出现在包括眼睛，鼻子，上颚，手和脚的骨骼特征以及视力，听力和智力发育受损的综合征中。大约85％的病例是非综合征性散发性病例，出现在从头结构基因组重排或单核苷酸变异后，而其余病例则由孟德尔遗传后的综合征性病例组成。通过核型分析，全基因组连锁，CNV分析以及全外显子组和全基因组测序，已经确定了颅骨突触症的许多候选基因，它们属于FGF，Wnt，BMP，Ras / ERK，ephrin，hedgehog，STAT和视黄酸信号通路。许多与颅突吻合相关的候选基因基于蛋白质-蛋白质或蛋白质-DNA相互作用形成功能网络。取决于该颅前突相关网络的哪个节点受到基因突变或基因表达模式的改变的影响，随之而来的是独特的颅前突综合征或一组表型。结构变异可能会改变一个或几个基因的剂量或破坏拓扑相关的染色质域内基因的基因组结构及其调控元件。这些可能通过单倍剂量不足，显性负性部分功能丧失，功能获得，上位性相互作用，发育过程中基因表达水平和模式的改变。这些突变的主要作用方式的分子机制可能包括同源蛋白伴侣或转录因子结合序列失去一个或几个结合位点。这种损失影响控制发育的功能网络内的相互作用，并因此导致表型如颅骨突触。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颖变异体，都被纳入了最近开发的颅突神经病诊断算法中。这种损失影响控制发育的功能网络内的相互作用，并因此导致表型如颅骨突触。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颖变异体，都被纳入了最近开发的颅突神经病诊断算法中。这种损失影响控制发育的功能网络内的相互作用，并因此导致表型如颅骨突触。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颖变异体，都被纳入了最近开发的颅突神经病诊断算法中。