Comprehensive analysis of the mutation spectrum in 301 German ALS families. Issue 8 (12th April 2018)

• Record Type: Journal Article
• Authors: Müller, Kathrin; Brenner, David; Weydt, Patrick; Meyer, Thomas; Grehl, Torsten; Petri, Susanne; Grosskreutz, Julian; Schuster, Joachim; Volk, Alexander E; Borck, Guntram; Kubisch, Christian; Klopstock, Thomas; Zeller, Daniel; Jablonka, Sibylle; Sendtner, Michael; Klebe, Stephan; Knehr, Antje; Günther, Kornelia; Weis, Joachim; Claeys, Kristl G; Schrank, Berthold; Sperfeld, Anne-Dorte; Hübers, Annemarie; Otto, Markus; Dorst, Johannes; Meitinger, Thomas; Strom, Tim M; Andersen, Peter M; Ludolph, Albert C; Weishaupt, Jochen H
• Other Names: author non-byline.; Weyen Ute author non-byline.; Hermann Andreas author non-byline.; Regensburger Martin author non-byline.; Winkler Jürgen author non-byline.; Linker Ralf author non-byline.; Winner Beate author non-byline.; Hagenacker Tim author non-byline.; Koch Jan Christoph author non-byline.; Lingor Paul author non-byline.; Göricke Bettina author non-byline.; Zierz Stephan author non-byline.; Jordan Berit author non-byline.; Baum Petra author non-byline.; Wolf Joachim author non-byline.; Winkler Andrea author non-byline.; Young Peter author non-byline.; Bogdahn Ulrich author non-byline.; Prudlo Johannes author non-byline.; Kassubek Jan author non-byline.; Danzer Karin author non-byline.
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 89:Issue 8(2018)
• Page Start: 817
• Page End: 827
• Publication Date: 2018-04-12
• Subjects: amyotrophic lateral sclerosis -- genetics -- whole exome sequencing; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2017-317611
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Objectives: Recent 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. Methods: Here 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. Results: 49% 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. Conclusions: We 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.