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

• Applicants: Professorin Dr. Kerstin Kutsche; Professor Dr. Martin Zenker
• Subject Area: Human Genetics
• Term: since 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259914611

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.

• DFG Programme: Research Grants