Abstract Details

Title Exome sequencing in carriers of the C9orf72 repeat mutation to identify pathogenic variants in other neurodegenerative genes

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 9-018

Objective

To explore pathogenic variants in other neurodegenerative genes in C9orf72 mutation carriers (C9+) and relationship of variants to clinical variables

Background Oligogenic inheritance is a possible explanation for the diversity of clinical features in C9orf72 mutation carriers, including age of onset (AOO) of disease and cognitive impairment.

Design/Methods Exome sequencing was carried out on 49 C9+ carriers (48 families) to identify previously described pathogenic variants from a list of genes reported to be associated with ALS or dementia in HGMD. 34 C9+ carriers were symptomatic and 15 were presymptomatic. Single nucleotide polymorphisms (SNPs) and small insertions/deletions (INDELs) with an ExAC allele frequency <0.0001 were identified using NHGRI VarSifter. AOO, cognitive impairment, and patrilineal/matrilineal inheritance in variant carriers were compared to non-carriers.

Results

741 SNPs and INDELs were identified in VarSifter. 11 C9+ carriers (22%) had a previously described pathogenic variant, and 2 C9+ carriers had variants in two genes. 7 C9+ carriers (2 presymptomatic, 2 ALS, 3 dementia) had a frameshift mutation in CD33, a myeloid gene associated with increased risk for AD. Other variants occurred in TBK1, SQSTM1, VAPB and GRN. 4 C9+ carriers were presymptomatic. Of 7 symptomatic C9+ carriers, the mean AOO=60 years, compared to 56 for the remaining members of the cohort, and published mean AOO=58 (Murphy et al). 4 C9+ dementia patients had AOO=62.3. No pattern was observed for gender or for inheritance lineage.

Conclusions

Variants in additional genes are common in C9orf72 mutation carriers, but in this sample do not fully explain phenotypic diversity. The later AOO of patients carrying additional pathogenic variants could suggest a protective effect. Further studies are needed to elucidate the mechanisms for C9orf72 phenotypic diversity.

REFERENCE Murphy, N.A. et al, Sci Rep. 2017, 7(1):2116.

Authors/Disclosures
Alice Tran PRESENTER	No disclosure on file
Mary Kay Floeter, MD, PhD (National Institute of Neurological Disorders and Stroke)	No disclosure on file

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