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.
- amyotrophic lateral sclerosis
- whole exome sequencing
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Contributors KM and JHW conceived the study. DB, PW, TMey, TG, SP, JG, JS, AEV, GB, CK, TK, DZ, SJ, MS, SK, AK, KG, JW, KGC, BS, A-DS, AH, MO, JD, TMei, TMS, PMA and ACL helped with the implementation. All authors contributed to the refinement of the study protocol and approved the final manuscript.
Funding This work was supported by grants from the German Society for Patients with Neuromuscular Diseases (DGM) and German Federal Ministry of Education and Research (BMBF; STRENGTH project and the German ALS network (MND-NET)). The work of AEV was funded by the Deutsche Forschungsgemeinschaft (DFG, VO 2028/1-1).
Competing interests None declared.
Patient consent Obtained.
Ethics approval This study was approved by the local medical ethics committees.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators Ute Weyen, Andreas Hermann, Martin Regensburger, Jürgen Winkler, Ralf Linker, Beate Winner, Tim Hagenacker, Jan Christoph Koch, Paul Lingor, Bettina Göricke, Stephan Zierz, Berit Jordan, Petra Baum, Joachim Wolf, Andrea Winkler, Peter Young, Ulrich Bogdahn, Johannes Prudlo, Jan Kassubek, Karin Danzer.