title: Rare autosomal copy number variations in early-onset familial Alzheimer's disease.
abstract: Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer's disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer's disease (AD). Using high-density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias.
authors.affiliation: Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: B V
authors.initials: BV
authors.lastname: Hooli
authors.affiliation: Department of Information Engineering, University of Brescia, Brescia, Italy.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Kovacs-Vajna
authors.affiliation: Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mullin
authors.affiliation: Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Blumenthal
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, Boston MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lange
authors.affiliation: Molecular Pathology Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mohapatra
authors.affiliation: Max-Planck Institute for Molecular Genetics, Neuropsychiatric Genetics Group, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bertram
authors.affiliation: Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree