Analysis of sequence variations in the LDL receptor gene in Spain: General gene screening or search for specific alterations?

Background: Familial hypercholesterolemia (FH) is a frequent form of autosomal-dominant hypercholesterolemia that predisposes to premature coronary atherosclerosis. FH is caused by sequence variations in the gene coding for the LDL receptor (LDLR). This gene has a wide spectrum of sequence variations, and genetic diagnosis can be performed by 2 strategies. Methods: Point variations and large rearrangements were screened along all the LDLR gene (promoter, exons, and flanking intron sequences). Results: We screened a sample of 129 FH probands from the Valencian Community, Spain, and identified 54 different LDLR sequence variations. The most frequent (10% of cases) was 111insA, and 60% of the variants had a frequency as low as 1%. A previously described method for detection of known sequence variations in the Spanish population by DNA array analysis allowed the identification of only similar to 50% of patients with a variant LDLR gene and similar to 40% of the screened samples. Conclusion: Our results indicate that the adequate procedure to identify LDLR sequence variations in outbreed populations should include screening of the entire gene. (c) 2006 American Association for Clinical Chemistry.