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Article ; Online: Validation of a next generation sequencing assay for BRCA1, BRCA2, CHEK2 and PALB2 genetic testing.

Sim, Wey Cheng / Lee, Chee Yang / Richards, Rebecca / Bettens, Karolien / Mottier, Violaine / Goh, Liuh Ling

2020 Volume 116, Page(s) 104483

Abstract: BRCA1, BRCA2, CHEK2 and PALB2 genes are associated with hereditary breast and ovarian cancer syndrome. Genetic testing of these genes is of increasing importance to guide therapeutic and management decisions. In this study, we evaluated the performance ... ...

Abstract	BRCA1, BRCA2, CHEK2 and PALB2 genes are associated with hereditary breast and ovarian cancer syndrome. Genetic testing of these genes is of increasing importance to guide therapeutic and management decisions. In this study, we evaluated the performance of a next generation sequencing (NGS) assay for the complete analysis of BRCA1, BRCA2, CHEK2 and PALB2 genes using Agilent's SureMASTR BRCA Screen that enabled the detection of single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variations (CNVs) in a single-tube PCR based library preparation. The results showed 100% sensitivity and specificity on a set of 52 known samples from de-identified patients and external quality assessment program. A concordance rate of 87.5% was achieved in the comparison of variant classification with the external laboratories. The high accuracy of the assay supports the use of SureMASTR BRCA Screen in clinical diagnostic laboratories (SureMASTR BRCA Screen is for research use only, not for use in diagnostic procedures).
MeSH term(s)	BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Checkpoint Kinase 2/genetics ; DNA Copy Number Variations/genetics ; Early Detection of Cancer/methods ; Fanconi Anemia Complementation Group N Protein/genetics ; Female ; Genetic Predisposition to Disease ; Genetic Testing ; Germ-Line Mutation/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; INDEL Mutation/genetics ; Male ; Middle Aged ; Neoplasm Metastasis ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Fanconi Anemia Complementation Group N Protein ; PALB2 protein, human ; Checkpoint Kinase 2 (EC 2.7.1.11) ; CHEK2 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2020-06-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207655-x
ISSN	1096-0945 ; 0014-4800
ISSN (online)	1096-0945
ISSN	0014-4800
DOI	10.1016/j.yexmp.2020.104483
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Article ; Online: Genetic insights in Alzheimer's disease.

Bettens, Karolien / Sleegers, Kristel / Van Broeckhoven, Christine

The Lancet. Neurology

2013 Volume 12, Issue 1, Page(s) 92–104

Abstract: In the search for new genes in Alzheimer's disease, classic linkage-based and candidate-gene-based association studies have been supplanted by exome sequencing, genome-wide sequencing (for mendelian forms of Alzheimer's disease), and genome-wide ... ...

Abstract	In the search for new genes in Alzheimer's disease, classic linkage-based and candidate-gene-based association studies have been supplanted by exome sequencing, genome-wide sequencing (for mendelian forms of Alzheimer's disease), and genome-wide association studies (for non-mendelian forms). The identification of new susceptibility genes has opened new avenues for exploration of the underlying disease mechanisms. In addition to detecting novel risk factors in large samples, next-generation sequencing approaches can deliver novel insights with even small numbers of patients. The shift in focus towards translational studies and sequencing of individual patients places each patient's biomaterials as the central unit of genetic studies. The notional shift needed to make the patient central to genetic studies will necessitate strong collaboration and input from clinical neurologists.
MeSH term(s)	Alzheimer Disease/diagnosis ; Alzheimer Disease/epidemiology ; Alzheimer Disease/genetics ; Animals ; Genetic Linkage/genetics ; Genetic Predisposition to Disease/epidemiology ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/trends ; Humans
Language	English
Publishing date	2013-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2079704-7
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(12)70259-4
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Article ; Online: Current status on Alzheimer disease molecular genetics: from past, to present, to future.

Bettens, Karolien / Sleegers, Kristel / Van Broeckhoven, Christine

Human molecular genetics

2010 Volume 19, Issue R1, Page(s) R4–R11

Abstract: Linkage studies, candidate gene and whole-genome association studies have resulted in a tremendous amount of putative risk genes for Alzheimer's disease (AD). Yet, besides the three causal genes-amyloid precursor protein and presenilin 1 and 2 genes-and ... ...

Abstract	Linkage studies, candidate gene and whole-genome association studies have resulted in a tremendous amount of putative risk genes for Alzheimer's disease (AD). Yet, besides the three causal genes-amyloid precursor protein and presenilin 1 and 2 genes-and one risk gene apolipoprotein E (APOE), no single functional risk variant was identified. Discussing the possible involvement of rare alleles and other types of genetic variants, this review summarizes the current knowledge on the genetic spectrum of AD and integrates different approaches and recent discoveries by genome-wide association studies.
MeSH term(s)	Alzheimer Disease/genetics ; Genetic Linkage ; Genetic Predisposition to Disease ; Humans
Language	English
Publishing date	2010-04-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddq142
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Article ; Online: Functional Changes in the Language Network in Response to Increased Amyloid β Deposition in Cognitively Intact Older Adults.

Adamczuk, Katarzyna / De Weer, An-Sofie / Nelissen, Natalie / Dupont, Patrick / Sunaert, Stefan / Bettens, Karolien / Sleegers, Kristel / Van Broeckhoven, Christine / Van Laere, Koen / Vandenberghe, Rik

Cerebral cortex (New York, N.Y. : 1991)

2017 Volume 27, Issue 7, Page(s) 3879

Language	English
Publishing date	2017--01
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	1077450-6
ISSN	1460-2199 ; 1047-3211
ISSN (online)	1460-2199
ISSN	1047-3211
DOI	10.1093/cercor/bhw117
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Zs.A 3235: Show issues

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Article ; Online: Functional Changes in the Language Network in Response to Increased Amyloid β Deposition in Cognitively Intact Older Adults.

Cerebral cortex (New York, N.Y. : 1991)

2016 Volume 26, Issue 1, Page(s) 358–373

Abstract: Word finding symptoms are frequent early in the course of Alzheimer's disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for ... ...

Abstract	Word finding symptoms are frequent early in the course of Alzheimer's disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for language and associative-semantic processing. Fifty-six community-recruited subjects (52-74 years), stratified for apolipoprotein E and brain-derived neurotrophic factor genotype, received a neurolinguistic assessment, (18)F-flutemetamol positron emission tomography, and a functional MRI of the associative-semantic system. The primary measure of amyloid load was the cerebral-to-cerebellar gray matter standardized uptake value ratio in a composite cortical volume of interest (SUVR(comp)). The primary outcome analysis consisted of a whole-brain voxelwise linear regression between SUVR(comp) and fMRI response during associative-semantic versus visuoperceptual processing. Higher activity in one region, the posterior left middle temporal gyrus, correlated positively with increased amyloid load. The correlation remained significant when only the word conditions were contrasted but not for pictures. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with SUVR(comp). A binary classification into amyloid-positive and amyloid-negative cases confirmed our findings. The left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden.
MeSH term(s)	Alzheimer Disease/diagnosis ; Alzheimer Disease/physiopathology ; Amyloid/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Brain/physiopathology ; Cognitive Dysfunction/diagnosis ; Cognitive Dysfunction/physiopathology ; Humans ; Language ; Magnetic Resonance Imaging/methods ; Positron-Emission Tomography/methods ; Semantics
Chemical Substances	Amyloid ; Amyloid beta-Peptides
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1077450-6
ISSN	1460-2199 ; 1047-3211
ISSN (online)	1460-2199
ISSN	1047-3211
DOI	10.1093/cercor/bhu286
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Article ; Online: Reduced secreted clusterin as a mechanism for Alzheimer-associated CLU mutations.

Bettens, Karolien / Vermeulen, Steven / Van Cauwenberghe, Caroline / Heeman, Bavo / Asselbergh, Bob / Robberecht, Caroline / Engelborghs, Sebastiaan / Vandenbulcke, Mathieu / Vandenberghe, Rik / De Deyn, Peter Paul / Cruts, Marc / Van Broeckhoven, Christine / Sleegers, Kristel

Molecular neurodegeneration

2015 Volume 10, Page(s) 30

Abstract: Background: The clusterin (CLU) gene has been identified as an important risk locus for Alzheimer's disease (AD). Although the actual risk-increasing polymorphisms at this locus remain to be identified, we previously observed an increased frequency of ... ...

Abstract	Background: The clusterin (CLU) gene has been identified as an important risk locus for Alzheimer's disease (AD). Although the actual risk-increasing polymorphisms at this locus remain to be identified, we previously observed an increased frequency of rare non-synonymous mutations and small insertion-deletions of CLU in AD patients, which specifically clustered in the β-chain domain of CLU. Nonetheless the pathogenic nature of these variants remained unclear. Here we report a novel non-synonymous CLU mutation (p.I360N) in a Belgian Alzheimer patient and have explored the pathogenic nature of this and 10 additional CLU mutations on protein localization and secretion in vitro using immunocytochemistry, immunodetection and ELISAs. Results: Three patient-specific CLU mutations in the β-chain (p.I303NfsX13, p.R338W and p.I360N) caused an alteration of the subcellular CLU localization and diminished CLU transport through the secretory pathway, indicative of possible degradation mechanisms. For these mutations, significantly reduced CLU intensity was observed in the Golgi while almost all CLU protein was exclusively present in the endoplasmic reticulum. This was further confirmed by diminished CLU secretion in HEK293T and HEK293 FLp-In cell lines. Conclusions: Our data lend further support to the contribution of rare coding CLU mutations in the pathogenesis of neurodegenerative diseases. Functional analyses suggest reduced secretion of the CLU protein as the mode of action for three of the examined CLU mutations. One of those is a frameshift mutation leading to a loss of secreted protein, and the other two mutations are amino acid substitutions in the disulfide bridge region, possibly interfering with heterodimerization of the α- and β-chain of CLU.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/epidemiology ; Alzheimer Disease/genetics ; Alzheimer Disease/physiopathology ; Amino Acid Substitution ; Belgium/epidemiology ; Biological Transport ; Clusterin/genetics ; Clusterin/secretion ; Cystine/chemistry ; Dimerization ; Endoplasmic Reticulum/metabolism ; Exons/genetics ; Female ; Frameshift Mutation ; Golgi Apparatus/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Male ; Mutation, Missense ; Protein Conformation ; Recombinant Fusion Proteins/metabolism ; Transduction, Genetic ; Transfection
Chemical Substances	CLU protein, human ; Clusterin ; Recombinant Fusion Proteins ; Cystine (48TCX9A1VT)
Language	English
Publishing date	2015-07-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1750-1326
ISSN (online)	1750-1326
DOI	10.1186/s13024-015-0024-9
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Article: No association between CALHM1 and risk for Alzheimer dementia in a Belgian population

Sleegers, Kristel / Brouwers, Nathalie / Bettens, Karolien / Engelborghs, Sebastiaan / van Miegroet, Helen / De Deyn, Peter P / Van Broeckhoven, Christine

Human mutation. 2009 Apr., v. 30, no. 4

2009

Abstract: A non-synonymous polymorphism, rs2986017 (p.P86L), in the newly characterized calcium homeostasis modulator 1 (CALHM1) gene located in the Alzheimer dementia (AD) linkage region on 10q24.33, was reported to increase risk of AD, and affect calcium ... ...

Abstract	A non-synonymous polymorphism, rs2986017 (p.P86L), in the newly characterized calcium homeostasis modulator 1 (CALHM1) gene located in the Alzheimer dementia (AD) linkage region on 10q24.33, was reported to increase risk of AD, and affect calcium homeostasis and amyloid β accumulation. We aimed to investigate the association between this functional polymorphism and AD in an independent study population. We genotyped rs2986017 in 362 Belgian AD patients and 519 ethnically matched control individuals. We found no evidence of association between rs2986017 and risk of disease, nor did we find an effect on onset age. Despite its functional properties, our study suggests the polymorphism does not contribute significantly to AD risk in the Belgian population.
Language	English
Dates of publication	2009-04
Size	p. E570-E574.
Publishing place	Wiley Subscription Services, Inc., A Wiley Company
Document type	Article
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.20990
Database	NAL-Catalogue (AGRICOLA)

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Article: Common variation in GRB-associated Binding Protein 2 (GAB2) and increased risk for Alzheimer dementia

Sleegers, Kristel / Bettens, Karolien / Brouwers, Nathalie / Engelborghs, Sebastiaan / van Miegroet, Helen / De Deyn, Peter P / Van Broeckhoven, Christine

Human mutation. 2009 Feb., v. 30, no. 2

2009

Abstract: GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onset Alzheimer dementia (AD) risk in carriers of the APOE ε4 allele in a genome-wide association analysis. We aimed to investigate this association in a well- ... ...

Abstract	GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onset Alzheimer dementia (AD) risk in carriers of the APOE ε4 allele in a genome-wide association analysis. We aimed to investigate this association in a well-characterized Belgian late-onset AD patient/control group: 528 Belgian AD patients (mean onset age 79.0±5.2 years, 70.2% females) and 601 ethnically matched control individuals (mean age 61.9±15.3 years, 57.1% females) were genotyped for 10 SNPs across the GAB2 locus. For 2 SNPs the most common genotype was associated with risk for AD, with the most significant result for rs4945261 [OR 1.49 (95%CI 1.04-2.15)]. After stratification by presence or absence of APOE ε4 these associations were present in APOE ε4 carriers only. When assessing the effect of APOE and rs4945261 in one model, rs4945261 did not show a main effect, but the joint risk effect of rs4945261-GG and APOE ε4 on AD was significant (OR 3.87, 95%CI 2.66-5.63; p=1.0E-12), with a deviation of 1.87 from the multiplicative model of interaction. Haplotype analyses showed evidence of association in the total (global psim 0.04) and APOE ε4+ (global psim 0.02) but not in the APOE ε4 - group (global psim 0.6). The association was driven by a higher frequency of the major haplotype in patients. Our data independently replicate an association between GAB2 and late-onset AD, which appears to be limited to APOE ε4 carriers.
Language	English
Dates of publication	2009-02
Size	p. E338-E344.
Publishing place	Wiley Subscription Services, Inc., A Wiley Company
Document type	Article
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.20909
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Article: SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population

Bettens, Karolien / Brouwers, Nathalie / Engelborghs, Sebastiaan / De Deyn, Peter P / Van Broeckhoven, Christine / Sleegers, Kristel

Human mutation. 2008 May, v. 29, no. 5

2008

Abstract: SORL1 has recently been identified as a major genetic contributor to increased risk for late-onset Alzheimer disease (AD). Here we aimed at replicating this finding in a large, well-characterized group of 550 Belgian late-onset AD patients and 637 ... ...

Abstract	SORL1 has recently been identified as a major genetic contributor to increased risk for late-onset Alzheimer disease (AD). Here we aimed at replicating this finding in a large, well-characterized group of 550 Belgian late-onset AD patients and 637 healthy control individuals using a gene-wide genotyping approach across the SORL1 locus. We observed significant associations, both for individual SNPs (SNPs 6, 8, 9, 10 and 27; p-values ranging from 0.001 to 0.040) and 3-SNP haplotypes (SNPs 5-6-7 and SNPs 25-26-27; p-values ranging from 0.008 to 0.035). Moreover, the associations at SNP 8, 9 and 10 represented a direct replication of the initial association data. Two signals in distinct regions of the gene were shown to be mutually independent, supporting allelic heterogeneity at the SORL1 locus in the Belgian population. Our findings confirm that genetic variants in SORL1 may be important risk factors for late-onset AD.
Language	English
Dates of publication	2008-05
Size	p. 769-770.
Publishing place	Wiley Subscription Services, Inc., A Wiley Company
Document type	Article
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.20725
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Article ; Online: Mutations in ABCA7 in a Belgian cohort of Alzheimer's disease patients: a targeted resequencing study.

Cuyvers, Elise / De Roeck, Arne / Van den Bossche, Tobi / Van Cauwenberghe, Caroline / Bettens, Karolien / Vermeulen, Steven / Mattheijssens, Maria / Peeters, Karin / Engelborghs, Sebastiaan / Vandenbulcke, Mathieu / Vandenberghe, Rik / De Deyn, Peter P / Van Broeckhoven, Christine / Sleegers, Kristel

The Lancet. Neurology

2015 Volume 14, Issue 8, Page(s) 814–822

Abstract: Background: ABCA7 was identified as a risk gene for Alzheimer's disease in genome-wide association studies (GWAS). It was one of the genes most strongly associated with risk of Alzheimer's disease in a Belgian cohort. Using targeted resequencing, we ... ...

Abstract	Background: ABCA7 was identified as a risk gene for Alzheimer's disease in genome-wide association studies (GWAS). It was one of the genes most strongly associated with risk of Alzheimer's disease in a Belgian cohort. Using targeted resequencing, we investigated ABCA7 in this cohort with the aim to directly detect rare and common variations in this gene associated with Alzheimer's disease pathogenesis. Methods: We did massive parallel resequencing of ABCA7 after HaloPlex target enrichment of the exons, introns, and regulatory regions in 772 unrelated patients with Alzheimer's disease (mean age at onset 74·6 years [SD 8·9]) recruited at two memory clinics in Flanders, Belgium, and 757 geographically matched community-dwelling controls (mean age at inclusion 73·9 years [8·0]). After bioinformatic processing, common variants were analysed with conditional logistic regression and rare variant association analysis was done in Variant Association Tools. To explore an observed founder effect, additional unrelated patients with Alzheimer's disease (n=183, mean age at onset 78·8 years [SD 6·0]) and control individuals (n=265, mean age at inclusion 56·9 years [10·8]) from the same cohort who had not been included in massive parallel resequencing because of insufficient biosamples were screened for the ABCA7 frameshift mutation Glu709fs with Sanger sequencing. The effect of loss-of-function mutations on ABCA7 expression was investigated with quantitative real-time PCR in post-mortem brains of patients (n=3) and control individuals (n=4); nonsense mediated mRNA decay was investigated in lymphoblast cell lines from three predicted loss-of-function mutation carriers from the cohort of 772 patients with Alzheimer's disease. Findings: An intronic low-frequency variant rs78117248 (minor allele frequency 3·8% in 58 patients with Alzheimer's disease and in controls 1·8% in 28 controls) showed strongest association with Alzheimer's disease (odds ratio 2·07, 95% CI 1·31-3·27; p=0·0016), and remained significant after conditioning for the GWAS top single nucleotide polymorphisms rs3764650, rs4147929, and rs3752246 (2·00, 1·22-3·26; p=0·006). We identified an increased frequency of predicted loss-of-function mutations in the patients compared with the controls (relative risk 4·03, 95% CI 1·75-9·29; p=0·0002). One frameshift mutation (Glu709fs) showed a founder effect in the study population, and was found to segregate with disease in a family with autosomal dominant inheritance of Alzheimer's disease. Expression of ABCA7 was reduced in the two carriers of loss-of-function mutations found only in patients with Alzheimer's disease (Glu709fs and Trp1214) compared with four non-carrier controls (relative expression 0·45, 95% CI 0·25-0·84; p=0·002) and in lymphoblast cell lines from three carriers of Glu709fs compared with those from two non-carrier controls. Interpretation:* We propose that a low-frequency variant can explain the association between ABCA7 and Alzheimer's disease, and the evidence of loss-of-function mutations in this risk gene suggests that partial loss-of-function of ABCA7 could be a potential pathogenetic mechanism of Alzheimer's disease. Funding: Belgian Science Policy Office Interuniversity Attraction Poles program P7/16, Alzheimer Research Foundation, King Baudouin Foundation AB Fund, Methusalem Excellence Program initiative of the Flemish Government, Flanders Impulse Program on Networks for Dementia Research, Research Foundation Flanders, Agency for Innovation by Science and Technology Flanders, University of Antwerp Research Fund, and European Union's Seventh Framework Programme for Research, Technological development and Demonstration (AgedBrainSYSBIO).
MeSH term(s)	ATP-Binding Cassette Transporters/genetics ; Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Belgium ; Cohort Studies ; Female ; Gene Frequency/genetics ; Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Mutation ; Polymorphism, Single Nucleotide ; Sequence Analysis, DNA/methods
Chemical Substances	ABCA7 protein, human
Language	English
Publishing date	2015-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2079704-7
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(15)00133-7
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