NeuroArray, A Custom CGH Microarray to Decipher Copy Number Variants in Alzheimer's Disease

Overview

Journal Curr Genomics

Publisher Bentham Science Publishers

Date 2018 Sep 28

PMID 30258280

Citations 1

Authors

Denis Cuccaro

Maria Guarnaccia

Rosario Iemmolo

Velia DAgata

Sebastiano Cavallaro

Affiliations

Soon will be listed here.

Abstract

Background: Copy Number Variants (CNVs) represent a prevailing type of structural variation (deletions or duplications) in the human genome. In the last few years, several studies have demonstrated that CNVs represent significant mutations in Alzheimer's Disease (AD) hereditability. Currently, innovative high-throughput platforms and bioinformatics algorithms are spreading to screening CNVs involved in different neurological diseases. In particular, the use of custom arrays, based on libraries of probes that can detect significant genomic regions, have greatly improved the resolution of targeted regions and the identification of chromosomal aberrations.

Objective: In this work, we report the use of NeuroArray, a custom CGH microarray useful to screening and further investigate the role of the recurring genomic aberrations in patients with confirmed or suspected AD.

Methods: The custom oligonucleotide aCGH design includes 641 genes and 9118 exons, linked to AD. The genomic DNA was isolated from blood samples of AD affected patients. The entire protocol of custom NeuroArray included digestion, labelling and hybridization steps as a standard aCGH assay.

Results: The NeuroArray analysis revealed the presence of amplifications in several genes associated with AD. In the coding regions of these genes, 14,586 probes were designed with a 348 bp median probe spacing. The majority of targeted AD genes map on chromosomes 1 and 10. A significant aspect of the NeuroArray design is that 95% of the total exon targets is covered by at least one probe, a resolution higher than CGH array platforms commercially available.

Conclusion: By identifying with a high sensitivity the chromosomal abnormalities in a large panel of AD-related genes and other neurological diseases, the NeuroArray platform is a valid tool for clinical diagnosis.

Citing Articles

Increased copy-number variant load of associated risk genes in sporadic cases of amyotrophic lateral sclerosis.

Guarnaccia M, Morello G, La Cognata V, La Bella V, Conforti F, Cavallaro S Cell Mol Life Sci. 2024; 81(1):316.

PMID: 39066921 PMC: 11335238. DOI: 10.1007/s00018-024-05335-8.

References

Farrer L, Cupples L, Haines J, Hyman B, Kukull W, Mayeux R . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997; 278(16):1349-56. View

Veltman J, Schoenmakers E, Eussen B, Janssen I, Merkx G, van Cleef B . High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am J Hum Genet. 2002; 70(5):1269-76. PMC: 447601. DOI: 10.1086/340426. View

Piluso G, Dionisi M, Del Vecchio Blanco F, Torella A, Aurino S, Savarese M . Motor chip: a comparative genomic hybridization microarray for copy-number mutations in 245 neuromuscular disorders. Clin Chem. 2011; 57(11):1584-96. DOI: 10.1373/clinchem.2011.168898. View

Veltman J, Jonkers Y, Nuijten I, Janssen I, van der Vliet W, Huys E . Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH. Am J Hum Genet. 2003; 72(6):1578-84. PMC: 1180319. DOI: 10.1086/375695. View

Sherrington R, Rogaev E, Liang Y, Rogaeva E, Levesque G, Ikeda M . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995; 375(6534):754-60. DOI: 10.1038/375754a0. View

Patitucci A, Muglia M, Magariello A, Gabriele A, Peluso G, Sprovieri T . Comparison of different techniques for detecting 17p12 duplication in CMT1A. Neuromuscul Disord. 2005; 15(7):488-92. DOI: 10.1016/j.nmd.2005.04.006. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

Nguyen D, Webber C, Ponting C . Bias of selection on human copy-number variants. PLoS Genet. 2006; 2(2):e20. PMC: 1366494. DOI: 10.1371/journal.pgen.0020020. View

Chapman J, Rees E, Harold D, Ivanov D, Gerrish A, Sims R . A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk. Hum Mol Genet. 2012; 22(4):816-24. PMC: 3554198. DOI: 10.1093/hmg/dds476. View

10.

Dhaene B, Vandesompele J, Hellemans J . Accurate and objective copy number profiling using real-time quantitative PCR. Methods. 2010; 50(4):262-70. DOI: 10.1016/j.ymeth.2009.12.007. View

11.

Brouwers N, Van Cauwenberghe C, Engelborghs S, Lambert J, Bettens K, Le Bastard N . Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol Psychiatry. 2011; 17(2):223-33. PMC: 3265835. DOI: 10.1038/mp.2011.24. View

12.

La Cognata V, Morello G, Gentile G, DAgata V, Criscuolo C, Cavalcanti F . A customized high-resolution array-comparative genomic hybridization to explore copy number variations in Parkinson's disease. Neurogenetics. 2016; 17(4):233-244. PMC: 5566182. DOI: 10.1007/s10048-016-0494-0. View

13.

Hooli B, Kovacs-Vajna Z, Mullin K, Blumenthal M, Mattheisen M, Zhang C . Rare autosomal copy number variations in early-onset familial Alzheimer's disease. Mol Psychiatry. 2013; 19(6):676-81. DOI: 10.1038/mp.2013.77. View

14.

Goate A, Chartier-Harlin M, Mullan M, Brown J, Crawford F, Fidani L . Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991; 349(6311):704-6. DOI: 10.1038/349704a0. View

15.

Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A . APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2005; 38(1):24-6. DOI: 10.1038/ng1718. View

16.

Redon R, Ishikawa S, Fitch K, Feuk L, Perry G, Andrews T . Global variation in copy number in the human genome. Nature. 2006; 444(7118):444-54. PMC: 2669898. DOI: 10.1038/nature05329. View

17.

Vasson A, Leroux C, Orhant L, Boimard M, Toussaint A, Leroy C . Custom oligonucleotide array-based CGH: a reliable diagnostic tool for detection of exonic copy-number changes in multiple targeted genes. Eur J Hum Genet. 2013; 21(9):977-87. PMC: 3746255. DOI: 10.1038/ejhg.2012.279. View

18.

Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K . Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991; 541(1):163-6. DOI: 10.1016/0006-8993(91)91092-f. View

19.

Li Y, Shaw C, Sheffer I, Sule N, Powell S, Dawson B . Integrated copy number and gene expression analysis detects a CREB1 association with Alzheimer's disease. Transl Psychiatry. 2012; 2:e192. PMC: 3565761. DOI: 10.1038/tp.2012.119. View

20.

Shaw-Smith C, Redon R, Rickman L, Rio M, Willatt L, Fiegler H . Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J Med Genet. 2004; 41(4):241-8. PMC: 1735726. DOI: 10.1136/jmg.2003.017731. View