Familial Hypercholesterolemia Sequencing Panel

Test Information

This panel of four genes is intended for patients with suspected or clinically diagnosed familial hypercholesterolemia, and it is performed by Next Generation Sequencing (NGS).

Turnaround Time

8 weeks

CPT Code(s)

81406 x 2, 81479




  • APOB
  • LDLR
  • PCSK9

Clinical Information

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.


Molecular testing is useful to confirm the diagnosis and to identify the disease-causing mutations within a family to allow for carrier testing.


Next Generation Sequencing


The current design of the familial hypercholesterolemia panel covers the coding region for all 4 genes and the flanking intronic sequences. This method allows for analysis of greater than 98% of the targeted sequence for the detection of nucleotide substitutions and small deletions and duplications. Large deletions and duplications will not be detected by this panel. Mutations and variants identified on the panel are confirmed with Sanger sequencing. All novel and apparently pathogenic changes are reported when found within the coding region as well as within 10 base pairs of each intron/exon boundary for each gene. Promoter and 3' untranslated sequences are not included in the current analysis. It should be noted that the current protocol is not specifically designed to detect copy number alterations and single exon deletions may require additional follow-up to determine whether or not they represent technical artifacts. Pathogenic variants in LDLR are identified in 60-80% of patients with familial hypercholesterolemia. Sequence-level changes are responsible for 90% of pathogenic variants in LDLR, while deletions in this gene account for 2.5-10% of cases. Please note that this analysis is not designed to detect copy number variants. Alterations in APOB are identified in 1-5% of patients, and variants in PCSK9 are responsible for up to 3% of cases. The prevalence of LDLRAP1 variants is considered very rare. We recommend further array-based testing to more accurately address the concerns of dosage alterations. The Cytogenetic Laboratory at GGC offers a high resolution microarray.

Specimen Requirements

The preferred sample type is peripheral blood collected in an EDTA (purple top) tube - at least 2-3ml for pediatric patients and 5-6ml for adult patients. Extracted DNA and saliva are also accepted for this test.

Transport Instructions

The specimen should be kept at room temperature and delivered via overnight shipping. If shipment is delayed by one or two days, the specimen should be refrigerated and shipped at room temperature. Do not freeze the specimen. Samples collected on Friday can be safely designated for Monday delivery.

Have Questions? Need Support?

Call our laboratory at 1-800-473-9411 or contact one of our Laboratory Genetic Counselors for assistance.
Robin Fletcher, MS, CGC
Falecia Thomas, MS, CGC

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