title: A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.
abstract: Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed.
authors.affiliation: Inserm U614, Faculté de Médecine, Rouen, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.forename: Solenn
authors.initials: S
authors.lastname: Legallic
authors.forename: David
authors.initials: D
authors.lastname: Wallon
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Flaman
authors.forename: Olivier
authors.initials: O
authors.lastname: Martinaud
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bombois
authors.forename: Adeline
authors.initials: A
authors.lastname: Rollin-Sillaire
authors.forename: Agnès
authors.initials: A
authors.lastname: Michon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Jérémie
authors.initials: J
authors.lastname: Pariente
authors.forename: Michèle
authors.initials: M
authors.lastname: Puel
authors.forename: Claire
authors.initials: C
authors.lastname: Paquet
authors.forename: Bernard
authors.initials: B
authors.lastname: Croisile
authors.forename: Catherine
authors.initials: C
authors.lastname: Thomas-Antérion
authors.forename: Martine
authors.initials: M
authors.lastname: Vercelletto
authors.forename: Richard
authors.initials: R
authors.lastname: Lévy
authors.forename: Thierry
authors.initials: T
authors.lastname: Frébourg
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype
chemical_list: D016564:Amyloid beta-Protein Precursor