title: Whole genome analysis in a consanguineous family with early onset Alzheimer's disease.
abstract: Early-onset Alzheimer's disease (EOAD) is a clinically and genetically heterogeneous condition in which the typical features appear significantly earlier in life (before 65 years). Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in autosomal dominant forms of EOAD. However, in about 50% of Mendelian cases and in most of the sporadic EOAD patients, no mutations have been found. We present clinical characteristics of an Israeli family comprising two affected siblings with EOAD born to neurologically healthy parents who were first cousins (both parents died after 90 years old). Sequence analysis of PSEN1, PSEN2, APP, TAU, PGRN, and PRNP failed to reveal any mutations in the affected siblings. Because the disease in this family is consistent with an autosomal recessive mode of inheritance we identified all homozygous regions identical by descent (IBD) in both siblings, by high-density SNP genotyping. We provide here the first catalog of autozygosity in EOAD and suggest that the regions identified are excellent candidate loci for a recessive genetic lesion causing this disease.
authors.affiliation: Memory Unit, Alzheimer's Laboratory, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. jclarimon@santpau.es
authors.forename: J
authors.initials: J
authors.lastname: Clarimón
authors.forename: R
authors.initials: R
authors.lastname: Djaldetti
authors.forename: A
authors.initials: A
authors.lastname: Lleó
authors.forename: R J
authors.initials: RJ
authors.lastname: Guerreiro
authors.forename: J L
authors.initials: JL
authors.lastname: Molinuevo
authors.forename: C
authors.initials: C
authors.lastname: Paisán-Ruiz
authors.forename: T
authors.initials: T
authors.lastname: Gómez-Isla
authors.forename: R
authors.initials: R
authors.lastname: Blesa
authors.forename: A
authors.initials: A
authors.lastname: Singleton
authors.forename: J
authors.initials: J
authors.lastname: Hardy
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D003241:Consanguinity; D005190:Family; D005260:Female; D005808:Genes, Recessive; D016678:Genome; D005838:Genotype; D006801:Humans; D007557:Israel; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA