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

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 repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer�...

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Bibliographic Details
Published in:Cold Spring Harbor molecular case studies 2019-12, Vol.5 (6), p.a003491
Main Authors: Cochran, J Nicholas, McKinley, Emily C, Cochran, Meagan, Amaral, Michelle D, Moyers, Bryan A, Lasseigne, Brittany N, Gray, David E, Lawlor, James M J, Prokop, Jeremy W, Geier, Ethan G, Holt, James M, Thompson, Michelle L, Newberry, J Scott, Yokoyama, Jennifer S, Worthey, Elizabeth A, Geldmacher, David S, Love, Marissa Natelson, Cooper, Gregory M, Myers, Richard M, Roberson, Erik D
Format: Article
Language:English
Subjects:
Age
Alleles
Alzheimer's disease
Apolipoprotein E
Dementia
Dementia disorders
Diagnostic systems
Frontotemporal dementia
Gene sequencing
Genetic diversity
Genetic variance
Genetics
Genomes
Genomics
Neurodegenerative diseases
Patients
Secretase
Signs and symptoms
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Summary: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 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 , , , and Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2-5) in , , , , , and All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two ε4 alleles. One patient had two 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 , , , , , , , , , , , and , 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.
ISSN:2373-2865
2373-2873
DOI:10.1101/mcs.a003491