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.

中文翻译：

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VWA2 中的化合物变体对阿尔茨海默病的贡献。

阿尔茨海默病是最常见的神经退行性痴呆诊断，在家族性和散发性患者中发病年龄早（≤65 岁）和晚（>65 岁）。3 种常染色体显性阿尔茨海默病基因，即淀粉样前体蛋白 (APP)、早老素 1 (PSEN1) 和早老素 2 (PSEN2) 的因果突变仅解释了 5%-10% 的早发患者，而大多数患者的基因未得到解决。为了发现潜在的缺失遗传学，我们使用了 17 名有充分记录的阿尔茨海默病临床诊断的早发患者的全基因组测序数据。在发现组中，平均发病年龄为 55.71 ± 6.83 岁（范围 37-65）。六名患者进行了脑部尸检，神经病理学证实了阿尔茨海默病。分析在一名患者中鉴定出的基因数据为纯合 p。包含 2 基因 (VWA2) 的 Von Willebrand 因子 A 结构域中的 V366M 错义突变。对来自佛兰德斯-比利时的阿尔茨海默病患者队列（n = 1148）中的 VWA2 编码区进行重新测序，其中包括 152 名早发患者和 996 名晚发患者，在 1 名早发患者和 3 名迟发患者中发现了额外的纯合和复合杂合错义突变。等位基因共享分析确定了复合杂合 VWA2 突变携带者之间的常见单倍型，表明有共同的祖先。总体而言，我们确定了 5 名纯合或复合杂合错义突变的患者携带者（5/1165；0.43 %），2 名早期患者（2/169；1.18 %）和 3 名晚发型患者（3/996；0.30 %）。患者中纯合和复合杂合错义突变的频率高于基于其组合单个等位基因计算的频率的预期。纯合/复合杂合错义突变携带者都没有常染色体显性阿尔茨海默病的家族史。我们的研究结果表明，VWA2 中的纯合和复合杂合错义突变可能导致散发性患者患阿尔茨海默病的风险。