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Papers In Press, published online ahead of print December 1, 2004
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Department of Vascular Biology Research Group, Robarts Research Institute, London, Ontario N6A 5K8
Corresponding Author: hegele{at}robarts.ca
Autosomal dominant (AD) familial hypercholesterolemia (FH, MIM 143890) typically results from mutations in the low-density lipoprotein (LDL) receptor gene (LDLR), which are commonly diagnosed using exon-by-exon screening methods, such as exon-by-exon sequence analysis (EBESA) of genomic DNA (gDNA). However, many patients with FH have no LDLR mutation identified by this method. Part of the diagnostic gap is due to genetic heterogeneity of AD FH, but another possible explanation is inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions in LDLR. Multiplex ligation-dependent probe amplification (MLPA) is a new method that detects larger gDNA alterations that are overlooked by EBESA. We hypothesized that some FH patients with no LDLR mutation detectable by EBESA would have an abnormal LDLR MLPA pattern. In 70 unrelated FH patients, 44 had LDLR mutations detected by EBESA, including missense, RNA splicing, nonsense or small deletion mutations, while five had the APOB R3500Q mutation. Among the remaining 21 AD FH patients with apparently no LDLR mutation, we found abnormal LDLR MLPA patterns in 12 and demonstrated the deleted sequence in five of these. The findings indicate that MLPA may be a useful new adjunctive tool for the molecular diagnosis of FH.
Revised on December 1, 2004
Accepted on November 16, 2004
Multiplex ligation-dependent probe amplification identifies LDR abnromalities in familial hypercholesterolemia patients with apparently normal LDR sequence
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