Table 10. [Familial Hypercholesterolemia: Gene-Specific Laboratory Considerations]. - GeneReviews®

Gene ¹	Special Consideration
APOB	Intron distribution w/in APOB is unusual: 24 of the 29 introns occur in the 5' terminus. >50% of the protein is encoded by 7,572-bp exon 26, 1 of the largest exons reported in the human genome. 1 of the 2 main isoforms, apolipoprotein B-100, synthesized exclusively in the liver, is responsible for complications related to FH [Whitfield et al 2004].
LDLR	Exon 4 encodes LDLR type A repeats 3, 4, & 5, located in the ligand-binding domain. This region is considered a hot spot & has been reported to have the most disease-causing variants per nucleotide. Exons 2-8 & exon 14 contain a total of 60 highly conserved cysteine residues that are vital for proper protein folding & function [Chora et al 2022].
PCSK9	PCSK9 pathogenic variants are assoc w/both hypercholesterolemia & hypocholesterolemia. Gain-of-function pathogenic variants cause hypercholesterolemia by excessive degradation of LDLRs, ↓ing the amount of LDL-C removed from blood. Loss-of-function pathogenic variants cause hypocholesterolemia by ↑ing the number of LDLRs on the surface of liver cells, resulting in ↑ed removal of LDL-C from blood & ↓ed incidence of coronary artery disease [Cohen et al 2006, Pandit et al 2008].

Gene ¹

Special Consideration

APOB

Intron distribution w/in APOB is unusual: 24 of the 29 introns occur in the 5' terminus. >50% of the protein is encoded by 7,572-bp exon 26, 1 of the largest exons reported in the human genome. 1 of the 2 main isoforms, apolipoprotein B-100, synthesized exclusively in the liver, is responsible for complications related to FH [Whitfield et al 2004].

LDLR

Exon 4 encodes LDLR type A repeats 3, 4, & 5, located in the ligand-binding domain. This region is considered a hot spot & has been reported to have the most disease-causing variants per nucleotide. Exons 2-8 & exon 14 contain a total of 60 highly conserved cysteine residues that are vital for proper protein folding & function [Chora et al 2022].

PCSK9

PCSK9 pathogenic variants are assoc w/both hypercholesterolemia & hypocholesterolemia. Gain-of-function pathogenic variants cause hypercholesterolemia by excessive degradation of LDLRs, ↓ing the amount of LDL-C removed from blood. Loss-of-function pathogenic variants cause hypocholesterolemia by ↑ing the number of LDLRs on the surface of liver cells, resulting in ↑ed removal of LDL-C from blood & ↓ed incidence of coronary artery disease [Cohen et al 2006, Pandit et al 2008].

From: Familial Hypercholesterolemia

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