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Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease
Julie Hoogmartens, Elisabeth Hens, Sebastiaan Engelborghs, Rik Vandenberghe, Peter-P De Deyn, Rita Cacace, Christine Van Broeckhoven, BELNEU Consortium. Neurobiology of aging, 2020-09-12
Topic: Genetics and APOE
Plain-language summary
Alzheimer's disease is the most frequent diagnosis of neurodegenerative dementia with early (≤65 years) and late (>65 years) onset ages in familial and sporadic patients. Causal mutations in 3 autosomal dominant Alzheimer genes, i.e. amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), explain only 5%-10% of early-onset patients leaving the majority of patients genetically unresolved. To discover potential missing genetics, we used whole genome sequencing data of 17 early-onset patients with well-documented clinical diagnosis of Alzheimer's disease. In the discovery group, the mean onset age was 55.71 ± 6.83 years (range 37-65). Six patients had a brain autopsy and neuropathology confirmed Alzheimer's disease. Analysis of the genetic data identified in one patient a homozygous p.V366M missense mutation in the Von Willebrand factor A domain containing 2 gene (VWA2). Resequencing of the VWA2 coding region in an Alzheimer's disease patient cohort from Flanders-Belgium (n = 1148), including 152 early and 996 late onset patients, identified additional homozygous and compound heterozygous missense mutations in 1 early and 3 late-onset patients. Allele-sharing analysis identified common haplotypes among the compound heterozygous VWA2 mutation carriers, suggesting shared ancestors. Overall, we identified 5 patient carriers of homozygous or compound heterozygous missense mutations (5/1165; 0.43 %), 2 in early (2/169; 1.18 %) and 3 in late-onset (3/996; 0.30 %) patients. The frequencies of the homozygous and compound heterozygous missense mutations in patients are higher than expected from the frequencies calculated based on their combined single alleles. None of the homozygous/compound heterozygous missense mutation carriers had a family history of autosomal dominant Alzheimer's disease. Our findings suggest that homozygous and compound heterozygous missense mutations in VWA2 might contribute to the risk of Alzheimer's disease in sporadic patients.
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APA 7th
Hoogmartens, J., Hens, E., Engelborghs, S., Vandenberghe, R., De Deyn, P.-P., Cacace, R., et al. (2021). Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease. Neurobiology of aging. https://doi.org/10.1016/j.neurobiolaging.2020.09.009
Vancouver
Hoogmartens J, Hens E, Engelborghs S, Vandenberghe R, De Deyn P.-P, Cacace R, et al. Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease. Neurobiology of aging. 2021. doi:10.1016/j.neurobiolaging.2020.09.009. PMID: 33023779.
BibTeX
@article{hoogmartens2021-33023779,
author = {Hoogmartens, Julie and Hens, Elisabeth and Engelborghs, Sebastiaan and Vandenberghe, Rik and De Deyn, Peter-P and Cacace, Rita and Van Broeckhoven, Christine and {BELNEU Consortium}},
title = {{Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease}},
journal = {Neurobiology of aging},
year = {2021},
doi = {10.1016/j.neurobiolaging.2020.09.009},
pmid = {33023779},
url = {https://doi.org/10.1016/j.neurobiolaging.2020.09.009}
}
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Key findings
- Overall, we identified 5 patient carriers of homozygous or compound heterozygous missense mutations (5/1165; 0.43 %), 2 in early (2/169; 1.18 %) and 3 in late-onset (3/996; 0.30 %) patients.
- Our findings suggest that homozygous and compound heterozygous missense mutations in VWA2 might contribute to the risk of Alzheimer's disease in sporadic patients.
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Study details
- Participants1,148
- Evidence strengthModerate
How this study scored 55/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomized / 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, multicenter collaboration and free to read, so those were left out: it earned 31 of the 56 points we could judge it on, which is 55 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurobiology of aging) |
| 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 | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,148 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33023779) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 31 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 31 of the 56 points we could judge it on is 55 out of 100. |
| Total | 55 / 100 | — |
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