title: Screening for familial APP mutations in sporadic cerebral amyloid angiopathy.
abstract: BACKGROUND
  Advances in genetic technology have revealed that variation in the same gene can cause both rare familial and common sporadic forms of the same disease. Cerebral amyloid angiopathy (CAA), a common cause of symptomatic intracerebral hemorrhage (ICH) in the elderly, can also occur in families in an autosomal dominant pattern. The majority of affected families harbor mutations in the Beta amyloid Peptide (Aβ) coding region of the gene for amyloid precursor protein (APP) or have duplications of chromosomal segments containing APP.
  
  
  RESULTS
  A total of 58 subjects with a diagnosis of probable or definite CAA according to validated criteria were included in the present study. We sequenced the Aβ coding region of APP in 58 individuals and performed multiplex ligation-dependent probe amplification to determine APP gene dosage in 60. No patient harbored a known or novel APP mutation or gene duplication. The frequency of mutations investigated in the present study is estimated to range from 0% to 8% in individuals with probable CAA in the general population, based on the ascertained sample size.
  
  
  CONCLUSIONS
  We found no evidence that variants at loci associated with familial CAA play a role in sporadic CAA. Based on our findings, these rare highly-penetrant mutations are unlikely to be seen in sporadic CAA patients. Therefore, our results do not support systematic genetic screening of CAA patients who lack a strong family history of hemorrhage or dementia.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Biffi
authors.forename: Anna
authors.initials: A
authors.lastname: Plourde
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.forename: Robert
authors.initials: R
authors.lastname: Onofrio
authors.forename: Eric E
authors.initials: EE
authors.lastname: Smith
authors.forename: Matthew
authors.initials: M
authors.lastname: Frosch
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Prada
authors.forename: James
authors.initials: J
authors.lastname: Gusella
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D016657:Cerebral Amyloid Angiopathy / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D016564:Amyloid beta-Protein Precursor