Familial hypercholesterolemia (FH) is typically an autosomal dominant disease characterized by the presence of high levels of plasma LDL (low density lipoproteins) cholesterol in the body, increasing the risk for premature coronary heart disease (CHD) and myocardial infarction.¹ The majority of autosomal dominant FH cases are associated with loss-of- function mutations in the gene for the low-density lipoprotein receptor (LDLR).² Affected individuals present high levels of plasma LDL cholesterol, which increases the risk of premature coronary artery disease, myocardial infarction, and atherosclerotic plaque formation. Defective LDL-receptors cause deposition of cholesterol in different parts of the body causing diseases such as xanthelasma (skin), xanthomas (tendons), and coronary arteries (atherosclerosis).^{3, 4}

There are approximately 1 in 500 individuals with heterozygous LDLR mutations and 1 in a million individuals with homozygous mutations in the general population.^{1, 2} Heterozygotes present a 2- to 3- fold elevation in plasma LDL-cholesterol and develop symptoms such as tendinous xanthomas, corneal arcus, and premature coronary artery disease.^2,4 Homozygotes also present planar xanthomas, with plasma LDLcholesterol increases 6- to 8-fold, and death from myocardial infarctions during the first two decades of life is common.⁵ As a result of founder effect, FH is much more common in some population groups such as French Canadians, Afrikaners, Lebanese, Finns, and Ashkenazi Jews.⁶

In addition to mutations in the LDLR gene, mutations in the APOB and PCSK9 genes contribute to two other types of familial hypercholesterolemia known as familial defective apolipoprotein B-100 (FDB)^{3, 7} and autosomal dominant hypercholesterolemia 3 (HCHOLA3), respectively. Apolipoprotein B-100 (APOB) is the major component of low density lipoproteins (LDL) and plays a crucial role in the binding of LDL with LDL receptors.⁷ These APOB mutations fall within the receptor binding domain of the gene and decrease the binding efficiency of lipoproteins with LDL receptors, leading to the accumulation of plasma LDL in FDB.

Proprotein convertase subtilisin kexin type 9 (PCSK9) is serine protease mainly expressed in the liver and the intestine, that acts as a chaperone that binds the LDLR, targeting it for internalization and degradation.⁹ PCSK9 can also act on the LDLR after biosynthesis before it reaches the basolateral surface of the cell.¹⁰ Gain-of-function mutations in PCSK9 lead to a reduction in LDLR levels, therefore causing hypercholesterolemia¹¹; while loss-of-function mutations are associated with a reduction of plasma LDL cholesterol level.¹² PCSK9 SNPs are unequally distributed in different ethnic groups. Besides the rare mutations implicated in ADH, some variants are functionally relevant in cholesterol regulation and their distribution and impact vary in different populations.¹³

Proper diet, exercise, and certain medications can aid in the treatment of FH. Heterozygous patients usually respond well with a combination of diet change and drugs (e.g. statins), while in some cases, surgery such as a liver transplant might be needed for homozygous patients.⁸ Proactive diagnosis, in combination with selective treatments, will help to decrease incidence and progression of FH and FDB effects.