Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL), the most common form of familial vascular dementia, is caused by mutations
of the NOTCH3 gene. Approximately two hundred pathogenic mutations have been reported within five
exons (exons 3, 4, 6, 11 and 19) which accounted for 78% of known mutations in worldwide
series. We reported twenty-one NOTCH3 pathogenic mutations (including five novel ones) identified in 53 index Italian patients.
Exons 4 (28%), 7 (21%) and 19 (24%) were the most frequently involved. To dissect
genetic heterogeneity, we analyzed five haplotyped tagging single nucleotide polymorphisms
(rs1044009, rs4809030, rs10426042, rs10423702 and rs3815188) in 95 patients, 39 unaffected
pedigree members and 50 healthy controls. SNPs were analyzed using the Illumina VeraCode
Universal Capture Beads technology by Allele Specific Primer Extension (ASPE). We
identified ten different haplotypes named H1–H10; H1 was the most common haplotype
in patients and controls and it was associated with at least twelve out of the twenty-one
mutations. Detected mutations were not associated to specific haplotypes while genotyping
was compatible with a possible founder effect for the novel p.S396C mutation which
clustered in a restricted geographical area of northeast Italy. The results added
on to the genetic heterogeneity of CADASIL and emphasized difficulties in designing
algorithms for molecular diagnosis.
Keywords
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Article info
Publication history
Published online: June 04, 2012
Accepted:
May 9,
2012
Received in revised form:
May 7,
2012
Received:
January 23,
2012
Identification
Copyright
© 2012 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
