Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.
Mol Genet Genomic Med
; 5(4): 418-428, 2017 Jul.
Article
em En
| MEDLINE
| ID: mdl-28717666
ABSTRACT
BACKGROUND:
Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants.METHODS:
We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS-relevant variants were cross-checked with population databases and case reports to critically assess whether they were "likely causal," "uncertain significance," or "unlikely causal."RESULTS:
Published ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers.CONCLUSIONS:
The use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Revista:
Mol Genet Genomic Med
Ano de publicação:
2017
Tipo de documento:
Article