Autosomal Dominant Hypercholesterolemia (ADH) is due to defects in the LDL receptor gene (LDLR), the apolipoprotein B-100 gene (APOB) or the proprotein convertase subtilisin/kexin type 9 gene (PCSK9). The aim of this study was to identify and to characterize the ADH-causative mutations in two Tunisian families. Analysis of the LDLR gene was performed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA) and by long range PCR and sequencing. The PCSK9 gene was analysed by direct sequencing and the APOB gene was screened for the most common mutation: p.Arg3527Gln. In the LDLR gene, we found two large deletions and characterized their exact extent and breakpoint sequences. The first one is a deletion of 12,684 bp linking intron 1 to intron 5: g.11205052_11217736del12684. The second deletion spans 2364 bp from intron 4 to 6: g.11216885_11219249del2364. Sequence analysis of each deletion breakpoint indicates that intrachromatid non-allelic homologous recombination (NAHR) between Alu elements is involved. These two large rearrangements in the LDLR gene are the first to be described in the Tunisian population, increasing the spectrum of ADH-causative mutations.
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