Hereditary Spastic Paraplegias (HSP) are genetically extremely heterogeneous. Nevertheless, even using the most modern genetic methods, genetic diagnosis can only be confirmed in just over half of all cases. We believe that this 'diagnostic gap' is not only caused by mutations in other, still unknown HSP genes, but that mutations in non-coding sections of the genome and unusual mutation types such as structural variants make a considerable contribution. These mutations escape the current standard analyses and will be systematically detected by means of targeted investigations (e.g. genome sequencing, transcriptome sequencing). Thus, this study will provide important impulses for the future orientation of diagnostic strategies in HSP and will increase the rate of molecular diagnosis of HSP.