Identification of novel genes implicated in Charcot-Marie-Tooth neuropathies using next generation full genome sequencing.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is clinically and genetically extremely heterogeneous. During the last two decades, molecular genetic studies have led to the successful identification of over 36 CMT-genes. Currently, only a few CMT-loci remain unresolved. This project addresses the identification of CMT-causing mutations and genes in two of them: DI-CMTA and CMT2G. Because of their private nature and large linkage intervals with high gene content, these loci so far represented a challenge for researchers. The immerging next generation sequencing technologies offer an attractive opportunity to tackle such orphan CMT-subtypes. Taking advantage of these new possibilities we aim to identify the disease-causing CMT-defects in DI-CMTA and CMT2G forms using whole genome sequencing. Once identified, we will search for additional pathogenic mutations in our extended collection of well characterized nuclear families affected with DI-CMT or CMT2, thus providing additional evidence for the causality of our findings. Our selected cohort will also be used for systematic screening of known DICMT/ CMT2-genes in order to delineate the mutation spectrum of both CMT-subtypes. Extensive genotypephenotype correlation will provide valuable insights concerning the clinical determinants of these entities and will aid future diagnostics and help uncover the neuropathy pathomechanisms.

Keywords:BIOCHEMISTRY, CHARCOT-MARIE-TOOTH DISEASE, NEUROPATHOLOGY

Disciplines:Genetics, Systems biology, Laboratory medicine, Medical systems biology, Molecular and cell biology, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing