Genetic Modifiers in Carriers of Repeat Expansions in the C9ORF72 Gene

Two fatal neurodegenerative diseases, frontotemporal dementia (FTD) and motor neuron disease (MND), demonstrate clinical, pathological, and genetic overlap.

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for FTD and MND, and represent the most frequent genetic cause of both diseases. Substantial phenotypic heterogeneity has been described in patients with these expansions. However, in C9ORF72 expansion carriers, FTD and/or MND-associated variants that modify disease risk, age at onset, or survival after onset have not been studied systematically.

Rosa Rademakers, Ph.D.

In a recent study in Molecular Neurodegeneration, Mayo Clinic researchers, first author Rosa Rademakers, Ph.D., Consultant, Division of Anatomic/Clinical Pathology at Mayo Clinic, set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.

During the study, Mayo Clinic researchers examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, variants previously implicated in FTD and/or MND were assessed; 36 variants were included in the analysis.

After adjustment for multiple testing, the analysis revealed three variants significantly associated with age at onset (rs7018487, rs6052771, and rs7403881, and six variants significantly associated with survival after onset (rs5848, rs7403881, rs13268953, the epsilon 4 allele, rs12608932, and rs1800435).

Variants identified through this study were previously reported to be involved in FTD and/or MND, but Mayo Clinic researchers are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion).

Although validation of findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense, and RNA-processing pathways. Additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.


Kelley Luedke

Kelley Luedke

Kelley Luedke is a Marketing Channel Manager at Mayo Clinic Laboratories. She is the principle editor and writer of Insights and leads social media and direct marketing strategy. Kelley has worked at Mayo Clinic since 2013. Outside of work, you can find Kelley running, traveling, playing with her kitty, and exploring new foods.