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Contribution of Homozygous and Compound Heterozygous Missense University of Groningen Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease BELNEU Consortium; Hoogmartens, Julie; Hens, Elisabeth; Engelborghs, Sebastiaan; Vandenberghe, Rik; De Deyn, Peter-P; Cacace, Rita; Van Broeckhoven, Christine Published in: Neurobiology of Aging DOI: 10.1016/j.neurobiolaging.2020.09.009 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2021 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): BELNEU Consortium, Hoogmartens, J., Hens, E., Engelborghs, S., Vandenberghe, R., De Deyn, P-P., Cacace, R., & Van Broeckhoven, C. (2021). Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease. Neurobiology of Aging, 99, 100.e17-100.e23. https://doi.org/10.1016/j.neurobiolaging.2020.09.009 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Neurobiology of Aging 99 (2021) 100.e9e100.e15 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer’s disease Julie Hoogmartensa,b,c, Elisabeth Hensa,b,c,d,e,f, Sebastiaan Engelborghsb,c,f, Rik Vandenbergheg, Peter-P. De Deynb,c,d, Rita Cacacea,b,c,*, Christine Van Broeckhovena,b,c,**, on behalf of the BELNEU Consortium a Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium b Institute Born-Bunge, Antwerp, Belgium c Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium d Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium e Department of Neurology, University Hospital Antwerp, Edegem, Belgium f Department of Neurology, University Hospital Brussel and Center for Neurosciences, Free University Brussels, Brussels, Belgium g Department of Neurology, University Hospitals Leuven and Department of Neurosciences, KU Leuven, Belgium article info abstract Article history: Alzheimer’s disease is the most frequent diagnosis of neurodegenerative dementia with early (65 years) Received 1 June 2020 and late (>65 years) onset ages in familial and sporadic patients. Causal mutations in 3 autosomal Received in revised form 2 September 2020 dominant Alzheimer genes, i.e. amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 Accepted 4 September 2020 (PSEN2), explain only 5%e10% of early-onset patients leaving the majority of patients genetically unre- Available online 12 September 2020 solved. 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 Keywords: Æ e ’ mean onset age was 55.71 6.83 years (range 37 65). Six patients had a brain autopsy and neuropa- Alzheimer s disease fi ’ fi Von Willebrand factor A domain containing thology con rmed Alzheimer s disease. Analysis of the genetic data identi ed in one patient a homo- 2 gene zygous p.V366M missense mutation in the Von Willebrand factor A domain containing 2 gene (VWA2). VWA2 Resequencing of the VWA2 coding region in an Alzheimer's disease patient cohort from Flanders-Belgium Homozygous and compound heterozygous (n ¼ 1148), including 152 early and 996 late onset patients, identified additional homozygous and missense mutations 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. Ó 2020 Elsevier Inc. All rights reserved. Funding: The research was in part supported by the Flemish Government 1. Introduction initiated Methusalem excellence program, the Flanders Impulse Program on Net- works for Dementia Research (VIND) and the Research Foundation Flanders (FWO); Progressive loss of memory and disturbances of cognitive Belgium. R.C. received a postdoctoral grant from the FWO. fi * Corresponding author at: VIB Center for Molecular Neurology, University of functions such as word- nding, spatial cognition and problem- Antwerp - CDE, Universiteitsplein 1, 2610 Antwerp, Belgium. Tel.: þ32 3 265 1039; solving clinically characterize Alzheimer’s disease (AD) (Cacace fax: þ323 625 84 10. et al., 2016). Extracellular accumulated amyloid-b (Ab) in plaques ** Corresponding author at: VIB Center for Molecular Neurology, University of and intracellular formation of neurofibrillary tangles of hyper- þ Antwerp - CDE, Universiteitsplein 1, 2610 Antwerp, Belgium. Tel: 32 3 265 1101; phosphorylated tau proteins are the neuropathological hallmarks of fax: þ323 625 84 10. E-mail addresses: [email protected] (R. Cacace), christine. AD (McKhann et al., 2011). These neuropathological characteristics [email protected] (C. Van Broeckhoven). are accompanied by gliosis and loss of neurons and synapses 0197-4580/$ e see front matter Ó 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.neurobiolaging.2020.09.009 J. Hoogmartens et al. / Neurobiology of Aging 99 (2021) 100.e9e100.e15 100.e10 (Cacace et al., 2016; Ringman et al., 2014). Among all dementia 57.93 Æ 6.33 years [range 29e65]) and 996 late onset (LO) AD pa- subtypes, AD is the most frequent and is affecting up to 75 % of tients (mean onset of 77.60 Æ 6.32 years [range 66e95]) (Table S1). dementia patients (Cacace et al., 2016; Koedam et al., 2010). Aging is Neuropathology at autopsy confirmed the clinical diagnosis of AD in the most prominent biological risk factor for developing AD at late 25 EOAD and 61 LOAD patients (Table S1). Sequencing of APP, PSEN1 age, and around 90 % of patients are diagnosed above 65 years and PSEN2 in the AD patient cohort identified in APP one pathogenic (Cacace et al., 2016). In the early-onset AD (EOAD) patients, diag- mutation in an EOAD patient (0.085 %) and in PSEN1 11 pathogenic nosed before 65 years, genetic risk is more prominent (Wingo et al., mutations in 8 EOAD and 3 LOAD patients (0.944%) (Perrone et al., 2012). Highly penetrant mutations in the amyloid precursor protein 2020)(Table S2). Overall, we identified known pathogenic muta- (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2), identified in tions in 1.030 % (12/1165) of the AD patients included in the cohort extended early-onset families with autosomal dominant trans- (Perrone et al., 2020). The cohort of control persons from the mission of AD, explain about 5%e10% of all EOAD patients (Cacace Flanders-Belgium region, included 759 age-matched individuals et al., 2016; Cruts et al., 1998; van Duijn et al., 1991). The apolipo- with a mean age at inclusion (AAI) of 74.70 Æ 6.56 years (range protein (APOE) ε4 allele is a major risk factor for AD at late age 65e100), with a Mini-Mental State Examination (MMSE) or Mon- (Cacace et al., 2016), increasing risk 3 times in heterozygous- and 15 treal Cognitive Assessment (MoCA) score 26 and without a family times in homozygous carriers (Corder et al., 1993). At early age, risk history of AD (Folstein et al., 1975; Nasreddine et al., 2005) is also increased in homozygous carriers and heterozygous ε4 car- (Table S1). Genomic DNA (gDNA) was available of all participants, riers with a positive family history of dementia (van Duijn et al., extracted from whole blood using standard laboratory procedures. 1994). Additionally, APOE alleles act as onset age modifiers in autosomal dominant AD families segregating a known pathogenic 2.2. Ethical assurance mutation (Cacace et al., 2016). Family studies showed that the onset age of the patient was earlier in the presence of an 43 allele and later All participants or their legal representative signed an informed in the presence of an 23 allele, which is a protective allele (Cacace consent for the participation in clinical, neuropathological and ge- et al., 2016; Sorbi et al., 1995). The use of large scaled genome- netic research. The ethical committee of the University Hospital of wide association studies (GWAS) and next generation sequencing Antwerp and the University of Antwerp (Antwerp, Belgium) fi (NGS) datasets ultimately identi ed additional genes with variable approved the clinical, neuropathological and genetics study genetic contributions to AD risk (e.g., [Cacace et al., 2019; Cuyvers protocols. and Sleegers, 2016; Guerreiro et al., 2012; Jansen et al., 2019; Zhou et al., 2019]).
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