Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease

BELNEU Consortium, Julie Hoogmartens, Elisabeth Hens, Sebastiaan Engelborghs, Rik Vandenberghe, Peter-P De Deyn, Rita Cacace, Christine Van Broeckhoven

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)100.e17-100.e23
Number of pages7
JournalNeurobiology of Aging
Volume99
Early online date12 Sep 2020
DOIs
Publication statusPublished - Mar 2021

Bibliographical note

Copyright © 2020 Elsevier Inc. All rights reserved.

Keywords

  • Alzheimer’s disease
  • Homozygous and compound heterozygous missense mutations
  • VWA2
  • Von Willebrand factor A domain containing 2 gene

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