This panel consists of four genes that have been associated with familial hypercholesterolemia. Familial hypercholesterolemia has an estimated prevalence of 1 in 200-250 individuals, and pathogenic variants in LDLR, APOB, PCSK9, or LDLRAP1 account for the majority of cases. This condition is associated with significant elevations in low-density lipoprotein (LDL) cholesterol. In addition, total cholesterol is typically increased (usually greater than 300 mg/dL in untreated individuals) with normal to slight elevations in triglycerides. Familial hypercholesterolemia is associated with increased risk of premature cardiovascular disease, specifically atherosclerosis, and symptoms include angina, heart attack, and rarely stroke. Other findings include a hazy ring along the outer rim of the iris known as corneal arcus and xanthomas, particularly of the hands and Achilles tendon.
Variants in LDLR, APOB, and PCSK9 are associated with autosomal dominant inheritance; however, biallelic pathogenic variants in LDLR can cause a rare autosomal recessive form of familial hypercholesterolemia. This form of familial hypercholesterolemia increases the prematurity of coronary artery disease. In these cases, childhood onset of signs and symptoms can occur due to dramatically elevated levels of LDL and total cholesterol. Physical findings include planar xanthomas, aortic stenosis, and corneal arcus, which is pathognomonic for familial hypercholesterolemia when it is identified during childhood.
LDLRAP1 is associated with autosomal recessive hypercholesterolemia. Features of this rare disorder include significant elevations of LDL and total cholesterol as well as triglycerides, often with childhood onset. Other physical signs may or may not be present.
Confirmation of pathogenic variants can assist with early detection, surveillance, and treatment, which may include dietary changes, medication, and surgical intervention to reduce the incidence or severity of cardiovascular complications. Identification of pathogenic variants can also lead to cascade testing for other at-risk family members.