The Delta>15 Kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction-based diagnostic assay and prevalence in Quebec.
Approximately one in 500 individuals in Western population has autosomal dominant familial hypercholesterolemia due to mutations in the low-density lipoprotein receptor (LDLR) gene. Screening for these mutations is hampered by their large number, except in founder populations. We identified the breakpoint of the >15 kb deletion involving the LDLR gene promoter and exon 1, responsible for more than 60% of French Canadian hypercholesterolemia cases, as well as the breakpoint of the 5 kb deletion of exons 2 and 3 that accounts for an additional 5% of cases. Both deletions appear to be because of homologous recombination by unequal crossing-over between the left arms of Alu repeats. Using RepeatMasker, we determined that 55% of the LDLR gene is composed of Alu elements; thus, it is not surprising that most LDLR rearrangements involve at least one Alu. Furthermore, we developed a rapid polymerase chain reaction-based assay for the French Canadian-1 (>15 kb) and French Canadian-5 (5 kb) hypercholesterolemia alleles. Screening a representative population sample of 943 French Canadian youths whose LDL cholesterol levels were above the 50th percentile allowed us to estimate the prevalence of the >15 kb allele as 0.11% (95% confidence interval, 0.03-0.38).
Simard
L R
LR
Centre de recherche, Hôpital Sainte-Justine and Université de Montréal, McGill University, 3175 Côte Sainte-Catherine, Montréal, Quebec, Canada H3T 1C5. simardlo@medclin.umontreal.ca
Viel
J
J
Lambert
M
M
Paradis
G
G
Levy
E
E
Delvin
E E
EE
Mitchell
G A
GA
D001483:Base Sequence; D002170:Canada / Q000453:epidemiology; D018703:Founder Effect; D005602:France / Q000208:ethnology; D005787:Gene Frequency; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D025202:Molecular Diagnostic Techniques; D016133:Polymerase Chain Reaction; D015995:Prevalence; D011792:Quebec / Q000453:epidemiology; D011973:Receptors, LDL / Q000235:genetics; D017384:Sequence Deletion
D011973:Receptors, LDL