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We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with  C9orf72  repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41–76). Fifty percent 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 and Genomics standards, including variants in  APP ,  C9orf72 ,  CSF1R , and  MAPT . Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2–5) in  ABCA7 ,  AKAP9 ,  GBA ,  PLD3 ,  SORL1 , and  TREM2 . All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two  APOE  ε4 alleles. One patient had two  APOE  ε4 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) in  ABI3 ,  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 frequently identified multiple established or possible contributory alleles. These observations add support for an oligogenic model for early-onset dementia.

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