Genetic Variants Associated with the Age of Onset Identified by Whole-Exome Sequencing in Fatal Familial Insomnia
Katrin Thüne,
Matthias Schmitz,
John Wiedenhöft,
Orr Shomroni,
Stefan Göbel,
Timothy Bunck,
Neelam Younas,
Saima Zafar,
Peter Hermann,
Inga Zerr
Affiliations
Katrin Thüne
Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany
Matthias Schmitz
Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany
John Wiedenhöft
Scientific Core Facility Medical Biometry and Statistical Bioinformatics, University Medical Center Goettingen, 37075 Goettingen, Germany
Orr Shomroni
NGS-Core Unit for Integrative Genomics, Institute of Human Genetics, University Medical Center Goettingen, 37075 Goettingen, Germany
Stefan Göbel
Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany
Timothy Bunck
Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany
Neelam Younas
Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany
Saima Zafar
Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany
Peter Hermann
Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany
Inga Zerr
Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany
Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease with a wide variability in age of onset. Its causes are not known. In the present study, we aimed to analyze genetic risk factors other than the prion protein gene (PRNP), in FFI patients with varying ages of onset. Whole-exome sequencing (WES) analysis was performed for twenty-five individuals with FFI (D178N-129M). Gene ontology enrichment analysis was carried out by Reactome to generate hypotheses regarding the biological processes of the identified genes. In the present study, we used a statistical approach tailored to the specifics of the data and identified nineteen potential gene variants with a potential effect on the age of onset. Evidence for potential disease modulatory risk loci was observed in two pseudogenes (NR1H5P, GNA13P1) and three protein coding genes (EXOC1L, SRSF11 and MSANTD3). These genetic variants are absent in FFI patients with early disease onset (19–40 years). The biological function of these genes and PRNP is associated with programmed cell death, caspase-mediated cleavage of cytoskeletal proteins and apoptotic cleavage of cellular proteins. In conclusions, our study provided first evidence for the involvement of genetic risk factors additional to PRNP, which may influence the onset of clinical symptoms in FFI.
