Genome sequencing for early-onset dementia: high diagnostic yield and frequent observation of multiple contributory alleles

Abstract

ABSTRACTWe assessed the utility of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along withC9orf72repeat expansion testing. All returned sequencing results were Sanger validated clinically. Prior clinical diagnoses included Alzheimer’s disease, frontotemporal dementia, and unspecified dementia. The mean age-of-onset was 54 (41–76). 50% of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics standards, including variants inAPP,C9orf72,CSF1R, andMAPT. Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of about 2–5) inABCA7,AKAP9,GBA,PLD3,SORL1, andTREM2. All six patients harboring these moderate penetrance variants but not P/LP variants also had one or twoAPOEε4 alleles. One patient had twoAPOEε4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) inABI3, ADAM10, ARSA, GRID2IP, MME, NOTCH3, PLCD1, PSEN1, TM2D3, TNK1, TTC3, and VPS13C, also often along with other variants. In summary, genome sequencing for early-onset dementia demonstrated high utility, with particular advantages where targeted testing may fail such as atypical variant-disease associations or presence of multiple moderate impact alleles. One or more established contributory alleles is often present in early-onset dementia, supporting an oligogenic model.