Analysis of 100 HSP Exomes and Characterization of Mutations in Known Autosomal Dominant Genes (P05.166)

Abstract

Objective: Comprehensive screening of all known autosomal dominant HSP genes in a large cohort of patients. Background Hereditary spastic paraplegias comprise a group of clinically and genetically heterogeneous neurodegenerative disorders that share the common clinical feature of lower limb spastic paraplegia. Ten genes causing autosomal dominant HSP are known to date, together explaining about 60% of cases. Knowledge about frequency of HSP subtypes and genotype-phenotype correlation is limited by the fact that most screenings so far are biased due to phenotypic pre-selection of the study cohort or inhomogeneous a priori genetic diagnostic testing. Design/Methods: We have screened a large cohort of autosomal dominant HSP patients for mutations in the most common HSP genes, including SPG3, SPG4 and SPG31. Mutation negative samples (n=100) were examined by whole exome sequencing. Sanger sequencing and segregation analysis were used to validate results. Results: More than hundred rare conserved coding variants were identified in known autosomal dominant HSP genes. The variants were further evaluated in regard to functional impact and segregation. Mutations in several rare autosomal dominant HSP genes as well as unusual phenotypes in patients with mutations in known HSP genes are described, including mutations in KIF5A, RTN2 and SETX. Conclusions: We have developed an advanced pipeline for analysis of known autosomal dominant HSP genes using whole exome sequencing. A comprehensive overview over mutational and phenotypic spectrum of autosomal dominant HSP is given. About 30% of autosomal dominant HSP cases cannot be explained by mutations in currently known autosomal dominant HSP genes, indicating the need for further studies to discover new HSP disease genes. Supported by: The National Institute of Health (grants 1R01NS072248-01 and 1 R01 NS352767) and the German HSP-Selbsthilfegruppe e.V. Disclosure: Dr. Schuele has nothing to disclose. Dr. Gonzalez has nothing to disclose. Dr. Powell has nothing to disclose. Dr. Klimpe has nothing to disclose. Dr. Klebe has nothing to disclose. Dr. Otto has nothing to disclose. Dr. Klopstock has received personal compensation for activities with Gerson Lehrman Group as a consultant. Dr. Speziani has nothing to disclose. Dr. Young has nothing to disclose. Dr. Schoels has received research support from Deutsche Forschungsgemeinschaft, German Research Council, Leukonet, mitoNET, EUROSPA, RISCA, and the HSP-Selbsthilfegruppe Deutschland eV. Dr. Zuchner has received license fee payments from Athena Diagnostics.