Publications about genetic testing for metabolic disorders
  1. Familial hypercholesterolemia panel

Familial hypercholesterolemia panel

September 24, 2018

Disease summary:

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by severe elevations in total cholesterol and low-density lipoprotein cholesterol levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. FH is the most common inherited cardiovascular disease, and it accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. Xanthomas around the eyelids and within tendons are frequently associated with FH and can be a helpful clinical sign. The major laboratory finding in FH-affected patients is extreme hypercholesterolemia, with low-density lipoprotein cholesterol levels. The most common cardiovascular disease in patients with FH is coronary artery disease, which may manifest as angina and myocardial infarction and more rarely stroke 1, 2, 3,.

An estimated 70%-95% of FH result from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9) 6. Recently, pathogenic variants in GHR, encoding growth hormone receptor, have been associated with a familial form of hypercholesterolemia 7 (Table 1).


Autosomal dominant

1/200 to 1/250 1, 1/10 in older Amish 2, 1/85 in Christian Lebanese 3, 1/72 to 1/100 in South African 3 and 1/67 in Ashkenazi Jewish population 3

Major clinical symptoms 1, 6:

  • Extreme hypercholesterolemia
  • Angina pectoris, myocardial infarction, peripheral vascular disease
  • Xanthomas around the eyelids and within the tendons of the elbows, hands, knees, and feet
  • Corneal arcus
  • Presence of the specific clinical features
  • Presence of elevated LDL-cholesterol levels in biochemical tests
  • Positive family history of hypercholesterolemia or coronary artery disease
  • Identification of a heterozygous pathogenic variant in one of the following genes (Table 1): APOB, GHR, LDLR, PCSK9.

There is no actual cure for familial hypercholesterolemia to date, but many symptomatic treatments can relieve symptoms 6, 7.

  • Lipid-lowering therapy with statin-based regimens significantly increases survival and reduces morbidity in FH-affected patients.
  • Additional medications such as ezetimibe, bile acid binding resins, or PCSK9 inhibitors are also highly beneficial.
  • Proper nutrition and physical activity, physical and occupational therapy and others.
  • 27-hydroxylase deficiency (cerebrotendonous xanthomatosis), caused by biallelic pathogenic variants in CYP27A1
  • Hyperlipoproteinemia type III (familial dysbetalipoproteinemia) caused by biallelic pathogenic variants in APOE.
  • Sitosterolemia (phytosterolemia), caused by biallelic pathogenic variants in either ABCG5 or ABCG8.
  • Polygenic hypercholesterolemia
  • Familial combined hyperlipidemia (FCHL)

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • Familial hypercholesterolemia NGS Panel Plus 
  • Familial hypercholesterolemia NGS Panel Plus + CNV which includes full gene sequencing and additionally detection of large deletions and duplications from the NGS data
  • Individuals with a positive family history of familial hypercholesterolemia
  • Individuals with most common symptoms of familial hypercholesterolemia (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of familial hypercholesterolemia can allow for genetic counseling and may direct medical management. Moreover, family members at risk can be identified.


Table 1: Overview of genes included in the Familial hypercholesterolemia panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
APOB 107730 Hypercholesterolemia, due to ligand-defective apo B; Hypobetalipoproteinemia AD, AR 25
GHR 600946 Hypercholesterolemia, familial, modifier of; Laron dwarfism; Growth hormone insensitivity, partial; Increased responsiveness to growth hormone AD, AR 8
LDLR 606945 Hypercholesterolemia, familial; LDL cholesterol level QTL2 AD 8
PCSK9 607786 Hypercholesterolemia, familial, 3; Low density lipoprotein cholesterol level QTL 1 5