Noonan综合征是一种常见的常染色体显性遗传病,以身材矮小为特征,先天性心脏病和面部畸形的发病率为1/1000至2500例活产。到目前为止,已证明几个基因通过RAS-MAP激酶途径参与转导信号的干扰和Noonan综合征的表现。描述的第一个基因是PTPN11,其次是SOS1,RAF1,KRAS,BRAF,NRAS,MAP2K1和RIT1,以及最近的SOS2,LZTR1和A2ML1等。逐步,Noonan综合征的大多数体征的病理生理学和分子病因学已得到证实,和遗传模式以及遗传咨询已经建立。在这次审查中,我们总结了在Noonan综合征中经常观察到的临床特征的数据,然后,我们描述了大多数Noonan综合征致病基因的分子病因和病理生理学.在本文的第二部分,我们评估了迄今为止在大多数筛查研究中报道的Noonan综合征致病基因的突变率.这篇评论应使临床医生和遗传学家全面了解Noonan综合征的分子方面及其致病基因突变事件的真实发生率。这也将有助于为未来的分子诊断研究奠定基础,以及新治疗策略的发展。
Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was PTPN11, followed by SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, and RIT1, and recently SOS2, LZTR1, and A2ML1, among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate laying the groundwork for future molecular diagnosis research, and the development of novel treatment strategies.