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Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles
Cochran JN, McKinley EC, Cochran M, Amaral MD, Moyers BA, Lasseigne BN, Gray DE, Lawlor JMJ et al.. Cold Spring Harbor molecular case studies, 2019-12-13
Topic: Amyloid, tau and blood-test diagnosis
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.
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APA 7th
Cochran, J. N., McKinley, E. C., Cochran, M., Amaral, M. D., Moyers, B. A., Lasseigne, B. N., et al. (2019). Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles. Cold Spring Harbor molecular case studies. https://doi.org/10.1101/mcs.a003491
Vancouver
Cochran JN, McKinley EC, Cochran M, Amaral MD, Moyers BA, Lasseigne BN, et al. Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles. Cold Spring Harbor molecular case studies. 2019. doi:10.1101/mcs.a003491. PMID: 31836585.
BibTeX
@article{cochran2019-31836585,
author = {Cochran, J. N. and McKinley, E. C. and Cochran, M. and Amaral, M. D. and Moyers, B. A. and Lasseigne, B. N. and Gray, D. E. and Lawlor, J. M. J. and others},
title = {{Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles}},
journal = {Cold Spring Harbor molecular case studies},
year = {2019},
doi = {10.1101/mcs.a003491},
pmid = {31836585},
url = {https://doi.org/10.1101/mcs.a003491}
}
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Key findings
- We assessed the results of genome sequencing for early-onset dementia.
- All returned sequencing results were Sanger-validated.
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Study details
- Participants32
- Effect size37.5%; 12.5%
- Evidence strengthLow
How this study scored 52/100
Published in a peer-reviewed journal. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 30 of the 58 points we could judge it on, which is 52 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Cold Spring Harbor molecular case studies) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2019 — within 10 year(s) of the newest study here |
| Sample size | 1 / 4 | 32 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 31836585) |
| Free to read | 2 / 2 | Free to read |
| Points | 30 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 30 of the 58 points we could judge it on is 52 out of 100. |
| Total | 52 / 100 | — |
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