Comprehensive analysis of the mutation spectrum in 301 German ALS families
| Autor: | Müller, Kathrin, Brenner, David, Kubisch, Christian, Klopstock, Thomas, Zeller, Daniel, Jablonka, Sibylle, Sendtner, Michael, Klebe, Stephan, Knehr, Antje, Günther, Kornelia, Weis, Joachim, Claeys, Kristl G, Weydt, Patrick, Schrank, Berthold, Sperfeld, Anne-Dorte, Hübers, Annemarie, Otto, Markus, Dorst, Johannes, Meitinger, Thomas, Strom, Tim M, Andersen, Peter M, Ludolph, Albert, Weishaupt, Jochen H, Meyer, Thomas, MND-NET, German ALS network, Weyen, Ute, Hermann, Andreas, Regensburger, Martin, Winkler, Jürgen, Linker, Ralf, Winner, Beate, Hagenacker, Tim, Koch, Jan Christoph, Lingor, Paul, Grehl, Torsten, Göricke, Bettina, Zierz, Stephan, Jordan, Berit, Baum, Petra, Wolf, Joachim, Winkler, Andrea, Young, Peter, Bogdahn, Ulrich, Prudlo, Johannes, Kassubek, Jan, Petri, Susanne, Danzer, Karin M, Grosskreutz, Julian, Schuster, Joachim, Volk, Alexander E, Borck, Guntram |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA Mutational Analysis Medizin German 0302 clinical medicine Superoxide Dismutase-1 Germany genetics Amyotrophic lateral sclerosis Exome sequencing Genetics Amyotrophic Lateral Sclerosis Whole Exome Sequencing TDP-43 protein human TBK1 protein human Protein-Serine-Threonine Kinases Pedigree genetics [Superoxide Dismutase-1] DNA-Binding Proteins Psychiatry and Mental health Editorial Commentary genetics [Amyotrophic Lateral Sclerosis] Mutation (genetic algorithm) symbols language Genotype genetics [Protein Serine-Threonine Kinases] genetics [DNA-Binding Proteins] Biology Protein Serine-Threonine Kinases genetics [Protein-Serine-Threonine Kinases] 03 medical and health sciences symbols.namesake medicine Humans Genetic Predisposition to Disease ddc:610 Gene genetics [C9orf72 Protein] C9orf72 Protein medicine.disease language.human_language 030104 developmental biology Mutation Mendelian inheritance RNA-Binding Protein FUS Surgery Neurology (clinical) Als genetics [RNA-Binding Protein FUS] 030217 neurology & neurosurgery |
| Zdroj: | Journal of neurology, neurosurgery, and psychiatry 89(8), 817-827 (2018). doi:10.1136/jnnp-2017-317611 Journal of Neurology, Neurosurgery, and Psychiatry J. Neurol. Neurosurg. Psychiatr. 89, 817-827 (2018) |
| DOI: | 10.1136/jnnp-2017-317611 |
| Popis: | ObjectivesRecent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.MethodsHere we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.ConclusionsWe here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe. |
| Databáze: | OpenAIRE |
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