Identification of novel causative genes for neuro-cardio-facio-cutaneous syndromes by whole exome sequencing and functional analysis of pathogenic mutations

Noonan、心面部皮肤(CFC)和Costello综合征属于一组遗传性疾病，由Ras-MAPK(丝裂原活化蛋白激酶)信号通路编码蛋白的基因杂合性胚系突变引起。这些临床实体被命名为神经-心脏-面部-皮肤(NCFC)综合征或Rasopathies。在大约30%的RA表型患者中，在已知基因中没有检测到致病突变。我们将在表型明确的患者及其父母(TRIO)中应用完整的外显子组测序，以确定NCFs综合征的新基因。通过在一大群患者(280人)中对这些候选基因进行测序，其中还包括表现出不同NCFC谱表型的个体，我们将确认所分析的基因是疾病基因，并确定相关的表型谱。我们项目的另一个重点将是对与NCFC综合征相关的突变进行功能分析。初步工作导致在已知或与RAS信号相关的新基因中鉴定出新的序列变异。我们将使用一系列成熟的生化和细胞生物学技术来研究以前发现的与疾病相关的新突变或通过整个外显子组测序发现的突变的功能后果。我们期望在NCFC综合征的遗传学及其潜在的病理生理学基础以及Ras-MAPK信号通路的复杂调控网络中获得有价值的见解。

Noonan, cardio-facio-cutaneous (CFC), and Costello syndrome belong to a group of genetic disorders which are caused by heterozygous germline mutations in genes encoding proteins of the RAS-MAPK (mitogen-activated protein kinase) signalling pathway. These clinical entities have been introduced under the name neuro-cardio-facio-cutaneous (NCFC) syndromes or RASopathies. In about 30% of patients with a RASopathy phenotype no pathogenic mutation is detected in the known genes. We will apply whole exome sequencing in patients with a clear-cut phenotype and their parents (trios) to identify novel genes for the NCFC syndromes. By sequencing these candidate genes in a large cohort of patients (280), that also includes individuals exhibiting variable phenotypes of the NCFC spectrum, we will confirm the analyzed genes as disease genes and determine the associated phenotypic spectrum. Another focus of our project will be the functional analysis of mutations associated with NCFC syndromes. Preliminary work led to the identification of novel sequence variations in known or new genes associated with RAS signalling. We will use a battery of well established biochemical and cell biological techniques to study the functional consequences of previously identified novel disease-associated mutations or those found by whole exome sequencing in this project. We expect to gain valuable insight in the genetics of the NCFC syndromes and their underlying pathophysiological basis as well as in the complex regulatory network of the RAS-MAPK signalling pathway.