Comprehensive analysis of the mutation spectrum in 301 German ALS families.
J Neurol Neurosurg Psychiatry
; 89(8): 817-827, 2018 08.
Article
en En
| MEDLINE
| ID: mdl-29650794
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteína FUS de Unión a ARN
/
Proteínas de Unión al ADN
/
Superóxido Dismutasa-1
/
Proteína C9orf72
/
Esclerosis Amiotrófica Lateral
/
Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Humans
País/Región como asunto:
Europa
Idioma:
En
Revista:
J Neurol Neurosurg Psychiatry
Año:
2018
Tipo del documento:
Article
País de afiliación:
Alemania