NGS to identify new genes in recessive HSP diseases and their functional validation


Institut für Neuropathologie 

Uniklinik-RWTH Aachen 


 Hereditary spastic paraplegias (HSPs) are not yet curable rare clinically and genetically heterogeneous group of upper motor neuron disorders, characterized by progressive spasticity and weakness of the lower limbs, due to corticospinal degeneration. The onset of the disease is very variable, embracing all the ages. At clinical level, HSPs are classified into pure forms and complex forms. All mode of inheritance were reported so far. Dozens of genes were localized or identified. However, several patients worldwide can not yet beneficiate for molecular diagnosis as they are negative for all the known genes.

We collected 15 large consanguineous families with motor neuron disorder affection. The families are clinically and Para-clinically well characterized. A written informed consent was obtained from all the patients and their examined relatives. Five of them were subjected to WES and none of them were positive for one of the known genes. For the 10 remaining families, we will combine highly parallel technologies consisting of genome linkage and homozygosity mapping in parallel with next generation sequencing; followed by a validation pipeline of bioinformatics tools. The data from the previous families and the new generated data will be compared in order to extract common regions and variants. Genetic validation consist first of the confirmation of the segregation of the mutation in the corresponding family members. Biological validation of the variants will be performed in basic models and cellular pathways could be thus identified.

Through this study, the first step is to identify new genes causing disease which will allow us to gain insight into the genetic basis of the disease. However, we intend to contribute to the better understanding of the physiopathology via the identification of critical pathways or their better elucidation. The main objective of the study is to identify therapeutic targets.

We have access to several facilities and collaborate with many institutes. The individuals involved in this project are very complementary which will ensure the feasibility of the project.