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  • e Application of Clinical Genetics

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The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations

isabel De Castro-Orós1 Miguel Pocoví2 Fernando Civeira1

1Lipid Unit and Laboratorio de investigación Molecular, Hospital Universitario Miguel Servet, instituto Aragonés de Ciencias de la Salud (i+CS), Zaragoza, Spain; 2Departamento. Bioquímica y Biología Molecular y Celular. Universidad de Zaragoza, instituto Aragonés de Ciencias de la Salud (i+CS), Zaragoza, Spain and Ciber de enfermedades Raras (CiBeReR), instituto de Salud Carlos iii, Spain

Abstract: Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by high plasma concentrations of low-density lipoprotein cholesterol (LDLc), tendon xanthomas, and increased risk of premature coronary heart disease. FH is one of the most common inherited disorders; there are 10,000,000 people with FH worldwide, mainly heterozygotes. The most common FH cause is mutations along the entire gene that encode for LDL receptor (LDLR) protein, but it has been also described that mutations in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 genes produce this phenotype. About 17%–33% of patients with a clinical diagnosis of monogenic hypercholesterolemia do not harbor any genetic cause in the known loci. Because FH has been considered as a public health problem, it is very important for an early diagnosis and treatment. Recent studies have demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced carotid artherosclerosis in patients with null than those with receptor-defective mutations. Since 2004, a molecular FH diagnosis based on a genetic diagnostic platform (Lipochip; Progenika-Biopharma, Derio, Spain) has been developed. This analysis completes the adequate clinical diagnosis made by physicians. Our group has recently proposed new FH guidelines with the intention to facilitate the FH diagnosis. The treatment for this disease is based on the benefit of lowering LDLc and a healthy lifestyle. Actually, drug therapy is focused on using statins and combined therapy with ezetimibe and statins. This review highlights the recent progress made in genetics, diagnosis, and treatment for FH. Keywords: LDLR, APOB, PCSK9, LDL cholesterol


The object of this review is to update the status of familial hypercholesterolemia (FH, MIMN#143890), with special consideration on the genetics and diagnosis. Heterozygous FH (heFH) is presented with high prevalence around the entire world, thus supposing elevated costs in health care.1 Although this disease has been exhaustively studied, new locus and mutations associated with FH are described each year. Taking all things together, it is important to research about the FH causes, and the effectiveness in the diagnosis and treatment.

Correspondence: Fernando Civeira Laboratorio de investigación Molecular, Hospital Universitario Miguel Servet, Avda isabel La Católica 1-3, 50009 Zaragoza, Spain Tel +34 976 76 55 00 Fax +34 976 56 65 69 email civeira@unizar.es

FH is an autosomal codominant inherited disorder of lipoprotein metabolism characterized by very high plasma concentrations of low-density lipopropotein cholesterol (LDLc), tendon xanthomas (TX), and increased risk of premature coronary heart disease (CHD).1 The penetrance of FH is almost 100%, which means that half of the offspring of an affected parent have a severely increased plasma cholesterol level from birth onwards, being both males and females equally affected.

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The Application of Clinical Genetics 2010:3 53–64 © 2010 De Castro-Orós et al, publisher and licensee Dove Medical Press Ltd.This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. 53

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