Comprehensive analysis of the mutation spectrum in 301 German ALS families.
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.
['Müller|Kathrin|K|', 'Brenner|David|D|', 'Weydt|Patrick|P|', 'Meyer|Thomas|T|', 'Grehl|Torsten|T|', 'Petri|Susanne|S|', 'Grosskreutz|Julian|J|', 'Schuster|Joachim|J|', 'Volk|Alexander E|AE|', 'Borck|Guntram|G|', 'Kubisch|Christian|C|', 'Klopstock|Thomas|T|', 'Zeller|Daniel|D|', 'Jablonka|Sibylle|S|', 'Sendtner|Michael|M|', 'Klebe|Stephan|S|', 'Knehr|Antje|A|', 'Günther|Kornelia|K|', 'Weis|Joachim|J|', 'Claeys|Kristl G|KG|', 'Schrank|Berthold|B|', 'Sperfeld|Anne-Dorte|AD|', 'Hübers|Annemarie|A|', 'Otto|Markus|M|', 'Dorst|Johannes|J|', 'Meitinger|Thomas|T|', 'Strom|Tim M|TM|', 'Andersen|Peter M|PM|', 'Ludolph|Albert C|AC|', 'Weishaupt|Jochen H|JH|', '|||']
D000690:Amyotrophic Lateral Sclerosis D000073885:C9orf72 Protein D004252:DNA Mutational Analysis D004268:DNA-Binding Proteins D020022:Genetic Predisposition to Disease D005838:Genotype D005858:Germany D006801:Humans D009154:Mutation D010375:Pedigree D017346:Protein Serine-Threonine Kinases D034702:RNA-Binding Protein FUS D000072105:Superoxide Dismutase-1
amyotrophic lateral sclerosis genetics whole exome sequencing