Jacques Genest, MD, Robert A

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Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia Jacques Genest, MD, Robert A. Hegele, MD, Jean Bergeron, MD, MSc, James Brophy, MD, PhD, Andre Carpentier, MD, Patrick Couture, MD, PhD, Jean Davignon, MD, Robert Dufour, MD, MSc, Jiri Frohlich, MD, Daniel Gaudet, MD, PhD, Milan Gupta, MD, Preetha Krisnamoorthy, MD, John Mancini, MD, Brian McCrindle, MD, Paolo Raggi, MD, Isabelle Ruel, PhD, Julie St-Pierre, MD, PhD Canadian Journal of Cardiology Volume 30, Issue 12, Pages 1471-1481 (December 2014) DOI: 10.1016/j.cjca.2014.09.028 Copyright © 2014 Canadian Cardiovascular Society Terms and Conditions

Figure 1 Physical findings (stigmata) in FH. (A) Bilateral xanthelasma on eyelids. (B) Bilateral arcus corneae, which are pathognomonic when detected by the fifth decade of life, but are nonspecific to FH by the eighth decade of life. (C) Arrows indicate xanthoma with the extensor tendon of the hand. (D) Arrows indicate xanthomas within the Achilles tendons. FH, familial hypercholesterolemia. Canadian Journal of Cardiology 2014 30, 1471-1481DOI: (10.1016/j.cjca.2014.09.028) Copyright © 2014 Canadian Cardiovascular Society Terms and Conditions

Figure 2 Genetics of FH. (A) Familial inheritance of heterozygous FH (HeFH). Squares and circles represent male and female individuals, respectively. Up to 1:250 matings in Canada involve an HeFH subject and a normolipidemic individual. Clinical and biochemical features of affected individuals are discussed in “Diagnosis of FH”, Tables 2, and Figure 1. Genotypic inheritance of FH-causing mutations and their cosegregation with the HeFH phenotype are shown below each pedigree symbol. Fifty percent of children of such a mating will have HeFH, which is usually fully expressed early in life. Because 50%, 25%, and 12.5% of first-, second-, and third-degree relatives of an affected individual will also have HeFH, systematic biochemical cascade screening of family members is considered by many to be a cost-effective approach to finding new cases. (B) Main genes causing FH. Chromosomal location of the main genes causing dominant HeFH and their chromosomal location: LDLR encoding the LDL receptor (approximately 95% of all causative mutations), APOB encoding apolipoprotein B (approximately 3% of all mutations), PCSK9 encoding proprotein convertase subtilisin kexin 9 (approximately 1% of all mutations), and some very rare genes are not shown. APOB, gene encoding apolipoprotein B; Chr, chromosome; FH, familial hypercholesterolemia; LDL, low-density lipoprotein; LDLR, gene encoding LDL receptor; PCSK9, gene encoding pro-protein convertase subtilisin/kexin type 9. Canadian Journal of Cardiology 2014 30, 1471-1481DOI: (10.1016/j.cjca.2014.09.028) Copyright © 2014 Canadian Cardiovascular Society Terms and Conditions

Figure 3 Diagnostic and treatment flow when familial hypercholesterolemia (FH) is suspected. APOB, gene encoding apolipoprotein B; C, cholesterol; LDL, low-density lipoprotein; LDLR, gene encoding LDL receptor; PCSK9, gene encoding pro-protein convertase subtilisin/kexin type 9. Canadian Journal of Cardiology 2014 30, 1471-1481DOI: (10.1016/j.cjca.2014.09.028) Copyright © 2014 Canadian Cardiovascular Society Terms and Conditions