Identification and functional characterisation of novel genes in hereditary neuropathies-II

Hereditary neuropathies, also known as Charcot-Marie-Tooth (CMT) syndrome, are the most common inherited disorders of the peripheral nervous system with an estimated prevalence of 1 in 2500. However, the frequency of these disorders still remains underestimated in Austria. Age at onset is usually during the first or second decade of life or sometimes later. Hallmark features are slowly progressive gait abnormalities and weakness in the hands due to mild to prominent muscle wasting in the distal parts of the upper and lower limbs. Distal sensory loss may also be present. Molecular genetic examinations in the past 20 years have shown marked genetic heterogeneity with the identification of mutations in multiple different genes. The knowledge of these previous studies has enabled first clinical trials in the past years. In this research project we aim to recruit CMT patients and families in all parts of Austria. We will perform detailed clinical, electrophysiological and genetic studies and will continue recruitment of patients for the CMT database. Our studies will help to make this common but still only little known inherited disorders of the peripheral nervous system public in Austria to achieve international standards. In several already known families with rare forms of CMT we will search for novel CMT genes using Next generation sequencing techniques and we will then carry out functional studies. Phenotype-genotype correlation studies will help us to improve guidelines for effective and successful testing of CMT patients in Austria. Finally, these studies will lead to a better understanding of the pathogenesis of the hereditary neuropathies and enables to develop therapies.

Twenty years ago we started to collect patients and families with hereditary neuropathies (Charcot-Marie-Tooth/CMT syndrome) in the South Eastern part of Austria, particularly in the province of Styria. Over many years our studies were supported and funded by FWF grants which enabled us to substantially expand clinical, electrophysiological and genetic studies to all parts of Austria. In the meantime more than 2000 CMT patients and 500 CMT families have been ascertained in the Austrian population. We also assessed CMT patients with autosomal recessive CMT disease. Epidemiological studies have been carried out in particular Austrian regions to define the frequency of different genetic subtypes of inherited neuropathies in the Austrian population. At present mutations in 40 different CMT genes have been identified suggesting considerable genetic heterogeneity also in Austria. During the past five years we recruited several further families with new CMT phenotypes. These were examined by genetic linkage studies using Affymetrix SNP arrays and Whole exome sequencing (WES). We identified potential novel gene loci. Using next generation sequencing techniques (NGS) like WES, which enables to sequence all exons of genes, helped us to identify new rare mutations in known CMT genes. Also, in collaboration with a German and English group we were able to identify a novel gene for HSN (PRDM12). Functional studies have been carried out and data have finally been published in the high ranked journal, Nature Genetics in 2015. Moreover, we were significantly involved in the identification of further novel CMT/dHMN genes such as BICD2, HINT1 and REEP1 for dHMN.