In:
Molecular Case Studies, Cold Spring Harbor Laboratory, Vol. 5, No. 6 ( 2019-12), p. a003491-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2373-2865
,
2373-2873
Language:
English
Publisher:
Cold Spring Harbor Laboratory
Publication Date:
2019
detail.hit.zdb_id:
2835759-0
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