OPTN p.Met468Arg and ATXN2 intermediate length polyQ extension in families with C9orf72 mediated amyotrophic lateral sclerosis and frontotemporal dementia

We have ascertained two families affected with familial amyotrophic lateral sclerosis (ALS) in which they both carry a hexanucleotide repeat expansion in the C9orf72 gene, specifically in individuals who also presented with frontotemporal dementia (FTD) or behavioral variant FTD (bvFTD). While some reports attribute this phenotypic heterogeneity to the C9orf72 expansion alone, we screened for additional genetic variation in known ALS-FTD genes that may also contribute to or modify the phenotypes. We performed genetic testing consisting of C9orf72 hexanucleotide expansion, ATXN2 polyglutamine (polyQ) expansion, and targeted next generation sequencing using the ONDRISeq, a gene panel consisting of 80 genes known to be associated with neurodegenerative diseases such as ALS, FTD, Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment. In addition to the C9orf72 expansion, we observed an ATXN2 polyQ intermediate length expansion, and OPTN p.Met468Arg in patients who exhibited ALS and FTD or bvFTD. We conclude that the C9orf72 expansion likely explains much of the ALS-FTD phenotype; however, inheritance of these additional variants likely modifies the disease course and may provide further evidence for biologically relevant oligogenic inheritance in ALS.