Received on January 27, 2006
Accepted on March 24, 2006

Molecular Diagnostics and Genetics

Analysis of Sequence Variations in the LDL Receptor Gene in Spain: General Gene Screening or Search for Specific Alterations?

¹ Laboratorio de Estudios Geneticos, Fundacion de Investigacion HCUV, Hospital Clinico Universitario de Valencia, Valencia, Spain
² Service of Endocrinology and Nutrition, Hospital Clinico Universitario de Valencia, University of Valencia, Valencia, Spain

^* To whom correspondence should be addressed. E-mail: felipe.chaves{at}uv.es.

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 50% of patients with a variant LDLR gene and 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.