title: Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a genetically complex disorder for which the definite diagnosis is only accomplished postmortem. Mutations in 3 genes (APP, PSEN1, and PSEN2) are known to cause AD, but a large number of familial cases do not harbor mutations in these genes and several unidentified genes that contain disease-causing mutations are thought to exist. We performed whole exome sequencing in a Turkish patient clinically diagnosed with Alzheimer's disease from a consanguineous family with a complex history of neurological and immunological disorders and identified a mutation in NOTCH3 (p.R1231C), previously described as causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Complete screening of NOTCH3 in a cohort of 95 early onset AD cases and 95 controls did not reveal any additional pathogenic mutations. Although the complex history of disease in this family precluded us to establish segregation of the mutation found with disease, our results show that exome sequencing is a rapid, cost-effective and comprehensive tool to detect genetic mutations, allowing for the identification of unexpected genetic causes of clinical phenotypes. As etiological based therapeutics become more common, this method will be key in diagnosing and treating disease.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rita João
authors.initials: RJ
authors.lastname: Guerreiro
authors.forename: Ebba
authors.initials: E
authors.lastname: Lohmann
authors.forename: Emma
authors.initials: E
authors.lastname: Kinsella
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Brás
authors.forename: Nga
authors.initials: N
authors.lastname: Luu
authors.forename: Nicole
authors.initials: N
authors.lastname: Gurunlian
authors.forename: Burcu
authors.initials: B
authors.lastname: Dursun
authors.forename: Basar
authors.initials: B
authors.lastname: Bilgic
authors.forename: Isabel
authors.initials: I
authors.lastname: Santana
authors.forename: Hasmet
authors.initials: H
authors.lastname: Hanagasi
authors.forename: Hakan
authors.initials: H
authors.lastname: Gurvit
authors.forename: Jesse Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Catarina
authors.initials: C
authors.lastname: Oliveira
authors.forename: Murat
authors.initials: M
authors.lastname: Emre
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014421:Turkey
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch