Session Information
Date: Monday, September 23, 2019
Session Title: Genetics
Session Time: 1:45pm-3:15pm
Location: Les Muses Terrace, Level 3
Objective: To develop molecular assays for determining the influence of hypermethylation on age of onset for C9ORF72 carriers.
Background: Hexanucleotide repeats of GGGGCC in C9ORF72 is the most common genetic cause for ALS, FTD and ALS/FTD and PD cases are also found. Currently there is not reliable biomarkers in c9ORF72 carriers and several groups attempted to assess whether the hypermethylation of c9orf72 can be a clinical modifier of disease, but very few significant correlations have been identified.
Method: We developed three different assays, one for screening MS-HRM and two quantitative (duplex-DDPCR) for c9-methylation.
Results: Two different regions in the c9orf72 gene were examined in c9ORF72-ALS DNA and two different duplex-DDPCR methods were developed. Both assays targeted regions located close to the c9-mutation and were found to be hypermethylated (p<0.00001). C9orf72 DNA methylation in ALS carriers (hex repeat>60 units) was significantly (p<0.0001) higher than in Swedish Parkinson carriers of c9 hex repeat expansion >30 repeats and healthy controls with <30 repeats. Both method detected more patients with c9 methylation than previous methods used in C9ALS and FTD and the methylation was higher in patients with late ALS onset (p<0.001). The influence on the age at onset showed a gradual effect when DNA was very high methylated (VH.METH), High methylated (H.METH) and intermediate (I.METH) low (L.METH) and very low methylated (V.L.METH). Moreover, c9-DNA methylation correlates with gene expression at both RNA and protein levels and trimethylated lysine residues within histones (H3K27).
Conclusion: In our study, we show that DNA methylation might be a clinical modifier in c9orf72 carriers. Confirming these exciting results in collected materials since early disease stages may provide of novel prodromal biomarker intrinsically related with the genetic defect c9orf72 hex repeat expansions. The methods we developed are promising tools for the investigating the role of epigenetic modifications as biomarker in c9orf72 carriers.
To cite this abstract in AMA style:
JM. Laffita-Mesa, CH. Kreidy, M. Paucar, P. Svenningsson. The potential modifier effect of C9orf72 DNA methylation in C9ORF72 carriers [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/the-potential-modifier-effect-of-c9orf72-dna-methylation-in-c9orf72-carriers/. Accessed May 16, 2025.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-potential-modifier-effect-of-c9orf72-dna-methylation-in-c9orf72-carriers/