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Clinical Chemistry 51: 1137-1144, 2005. First published May 12, 2005; 10.1373/clinchem.2004.045203
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Right arrow Molecular Diagnostics and Genetics
(Clinical Chemistry. 2005;51:1137-1144.)
© 2005 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Reliable Low-Density DNA Array Based on Allele-Specific Probes for Detection of 118 Mutations Causing Familial Hypercholesterolemia

Diego Tejedor1,a, Sergio Castillo1, Pilar Mozas1, Elisa Jiménez3, Mónica López3, M. Teresa Tejedor2, Marta Artieda4, Rodrigo Alonso5, Pedro Mata5, Laureano Simón3, Antonio Martínez3, Miguel Pocoví1 the Spanish FH Group

1 Departamento de Bioquímica y Biología Molecular y Celular, 2 Departamento de Anatomía, Embriología y Genética Animal, Universidad de Zaragoza, Zaragoza, Spain.
3 PROGENIKA BIOPHARMA S.A., Derio, Spain.
4 Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Zaragoza, Spain.
5 Unidad de Lípidos, Fundación Jiménez Díaz, Madrid, Spain.

aAddress correspondence to this author at: PROGENIKA BIOPHARMA, S.A., Edificio 801, Parque Tecnológico de Zamudio, 48160 Derio, Spain. Fax 34-94-406-4526; e-mail dtejedor{at}progenika.com.

Background: Patients with familial hypercholesterolemia (FH) have a high risk of premature cardiovascular disease (PCVD). Mutations in the LDL receptor (LDLR) gene and the R3500Q mutation in the apolipoprotein B (APOB) gene are known to cause FH, but lack of high-throughput methods makes routine genetic diagnosis difficult. The objective of this work was to develop a DNA array for large-scale identification of mutant LDLR alleles.

Methods: We developed a low-density oligonucleotide microarray to identify 118 DNA sequence variations (117 for the LDLR gene and 1 for the APOB gene). We verified specificity and sensitivity by analyzing 1180 previously sequenced DNA samples, and conducted a blind study screening 407 Spanish patients with a clinical diagnosis of FH.

Results: The DNA array confirmed the previous genotyping results in almost all cases. In the blind study, the microarray detected at least 1 mutation in 51% of the patients for whom clinical diagnosis was classified as certain according to Dutch FH-MEDPED criteria; it also identified mutations in 37% of those with a diagnosis of probable/possible FH, thus giving a definite diagnosis. Patients harboring null mutations had shorter PCVD-free survival times and higher relative risk of PCVD than patients with a missense mutation.

Conclusions: The proposed DNA array allows large-scale population screening and provides molecular information regarding mutation type and its correlation with clinical severity of FH, which can be used to develop therapeutic strategies.




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