Next Generation Sequencing diagnostics for HSPs

Germany leading in HSP gene testing


Researchers in Germany have developed an “HSP-Panel” that will provide HSPers with cutting-edge gene testing services. Based on next-generation sequencing (NGS), they have packed 38 HSP genes together with 50 other genes responsible for clinically similar diseases onto the panel. This means that almost all known HSP genes can be screened for in one single examination, in a much shorter time frame, and at around the same cost as the limited testing currently available.


Dr. Peter Bauer
Dr. Peter Bauer

The panel, developed by Dr. Rebecca Schuele and Prof. Dr. Peter Bauer, is expected to be approved for general use in Germany under their health insurance scheme in the near future for all families at risk of HSP.



Hereditary spastic paraplegias are challenging for diagnostic laboratories because overwhelming heterogeneity precluded comprehensive testing approaches in the past. With the advent of next generation sequencing, virtually all known HSP genes can be tested at once. This increases the expected diagnostic yield significantly, as we tended to analyze only one or a few “good” disease genes in the past.

After setting up a disease gene list for all known HSPs gene and several “HSP-related” genes, we develop a HaloPlex exon enrichment assay (Agilent) for 62 genes with > 150kb coding sequences for Illumina MiSeq V2 paired-end sequencing. A pilot study with 14, yet undiagnosed HSP patients revealed that we could sequence > 2/3 of these genes for all coding bases at more than 20 reads coverage. Mean coverage was 500-800 reads. A standard bioinformatic pipeline for mapping (stampy) and annotation (annovar) yielded a total of 82 ± 5 variants in our disease genes. Only 3 ± 2 variants were rare and therefore further evaluated as a potential cause for the spastic phenotype.

Interestingly, we identified three known HSP mutations in for patients (in NIPA1, ATL1, and KIF5A). Another three patients carried known heterozygous mutations for recessive diseases (in the GBA, and PANK2 gene, respectively). Whether these genotypes represent risk factors for HSP or rather have been detected by chance without any pathogenic involvement remains to be determined.

In conclusion, next-generation sequencing can provide high throughput diagnostics for HSPs by genotyping all known and potentially associated genes in these heterogenic diseases.


from a presentation by Peter Bauer, Institute of Medical Genetics and Applied Genomics, University of Tübingen, GER

Dresden, Germany, 22 March 2013.


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