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

Alzheimer’s disease is the most frequent diagnosis of neurodegenerative dementia with early (≤65 years) and late (>65 onset ages in familial sporadic patients. Causal mutations 3 autosomal dominant Alzheimer genes, i.e. amyloid precursor protein (APP), presenilin 1 (PSEN1) 2 (PSEN2), explain only 5%–10% early-onset patients leaving majority genetically unresolved. To discover potential missing genetics, we used whole genome sequencing data 17 well-documented clinical disease. In discovery group, mean age was 55.71 ± 6.83 years (range 37–65). Six had a brain autopsy neuropathology confirmed Analysis genetic identified one patient homozygous p.V366M missense mutation Von Willebrand factor A domain containing gene (VWA2). Resequencing VWA2 coding region an Alzheimer's cohort from Flanders-Belgium (n = 1148), including 152 996 patients, additional compound heterozygous late-onset Allele-sharing analysis common haplotypes among carriers, suggesting shared ancestors. Overall, 5 carriers or (5/1165; 0.43 %), (2/169; 1.18 %) (3/996; 0.30 The frequencies are higher than expected calculated based on their combined single alleles. None homozygous/compound family history Our findings suggest that might contribute to risk