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Familial Hypercholesterolemia: The Lipids or the Genes?

DOI: 10.1186/1743-7075-8-23

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In this review, we reconsider the clinical versus genetic nomenclature of FH in the literature. After we describe each of the genetic causes of FH, we summarize the known correlation with phenotypic measures so far for each genetic defect. We then discuss studies from different populations on the genetic and clinical diagnoses of FH to draw helpful conclusions on cost-effectiveness and suggestions for diagnosis.Familial Hypercholesterolemia (FH) (MIM #143890) is a genetic disease characterized by elevated LDL-Cholesterol (LDL-C), which deposits in the tissues causing the external manifestations of the disease, namely tendinous xanthomas, xanthelasmas, and corneal arcus. More importantly, LDL-C deposits in blood vessels leading to premature cardiovascular disease [1,2]. The patterns of inheritance of FH were first described by Khachadurian in Lebanon before the genes that contribute to the disease were known [3]. FH was defined as an autosomal dominant disease, with a clinical distinction based on phenotype severity of a "heterozygous" and a "homozygous" form, with serum LDL-C levels that are two times and four times the normal respectively [3]. The prevalence of the severe phenotype has been reported as 1 in a million in the general population, compared to the much more common mild form with a prevalence of 1 in 500 [1]. The prevalence has been reported to be ten times higher in certain populations with a presumed founder effect, such as the Lebanese, the French Canadians, and the South Afrikaners [1,2]. A less common autosomal recessive pattern of inheritance was also described in some of the initial Lebanese families [3].In 1986, the LDL receptor (LDLR) was discovered as the cause of Autosomal Dominant Hypercholesterolemia (ADH) [4]. It manifests a gene dosage effect such that the heterozygous and homozygous forms cause mild and severe phenotypes respectively. For years, ADH was thought of as a monogenetic disease. However, as more genotyping of FH patients was ca


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