• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The LDLR gene is associated with autosomal dominant familial hypercholesterolemia (FH) (MedGen UID: 5688). Generally, the presence of two pathogenic variants is associated with a severe form of FH commonly referred to as homozygous FH (HoFH) (MedGen UID: 468437).

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Pathogenic LDLR variants are associated with 60%-80% of clinical cases of familial hypercholesterolemia.

The LDLR gene encodes the low density lipoprotein receptor (LDLR), a cell surface protein involved in the absorption of low density lipoprotein cholesterol (LDL-C).

OMIM: 606945

Clinical condition
The LDLR gene is associated with autosomal dominant familial hypercholesterolemia (FH; MedGen UID: 5688). Generally, the presence of two pathogenic variants (homozygous or compound heterozygous) is associated with a severe form of FH, commonly referred to as homozygous FH (HoFH; MedGen UID: 468437).

FH is characterized by a very high level of low-density lipoprotein cholesterol (LDL-C) that can cause atherosclerotic plaque deposits and lead to premature coronary artery disease. Untreated individuals have a significantly increased risk of developing coronary heart disease (CHD; PMID: 21600525, 15177124). Plaque deposits can also be found in extravascular tissues, such as tendon and skin xanthoma and corneal arcus (PMID: 15177124). Untreated individuals with HoFH typically have marked hypercholesterolemia and are at risk of developing severe CHD, often in childhood or adolescence (PMID: 21986285).

Gene information
The LDLR gene encodes the low-density lipoprotein receptor (LDLR), a cell surface protein involved in the absorption of LDL-C and regulation of cholesterol synthesis. Pathogenic variants in LDLR either reduce the number of receptors or decrease the ability of LDLR to bind to LDL-C, resulting in an excess of LDL-C in the blood (PMID: 226968).

FH due to a pathogenic variant in LDLR has autosomal semi-dominant inheritance. This means that an individual with a single pathogenic variant has a 50% chance of passing the variant and predisposition to FH on to his/her offspring. Penetrance is incomplete (PMID: 27050191).

Individuals with two pathogenic variants—one in each copy of their LDLR genes—have HoFH and a more severe presentation. HoFH-affected individuals will pass one pathogenic LDLR variant and a predisposition for FH to all their children.

Additionally, individuals with LDLR-related FH and HoFH have a reproductive risk for children with HoFH. The chance of having a child with two pathogenic variants and a more severe clinical presentation depends on the carrier state of the individual and their partner.

Most cases of FH are inherited from a parent, but some may occur de novo (i.e., an individual with a pathogenic variant has parents who do not have it). Identification of a pathogenic variant allows for the recognition of at-risk relatives who can pursue testing for the familial variant.

The goal of management in FH is to reduce the level of serum LDL-C and thus the risk of CHD and myocardial infarction. Published guidelines include the following recommendations:

  • Lifestyle modifications: healthy diet, exercise, weight control, blood pressure control, and smoking cessation (PMID: 26510694, 24418289)
  • Aggressive pharmacologic therapies to lower LDL-C level, including statins (PMID: 26510694, 24418289)
    • Baseline levels of hepatic transaminases and creatine kinase should be obtained prior to initiation of treatment (PMID: 26510694).
  • LDL-C aphresis (PMID: 23461430, 26510694, 24418289)
  • Patients with well-controlled lipid levels can be followed by their primary care physician (PMID: 24418289).
  • Referral to a lipid specialist is recommended for patients with HoFH, high lipid levels that are difficult to control, and those who are at high risk for cardiac complications (PMID: 23461430, 24418289).
  • Women and girls of childbearing age should receive pre-pregnancy counseling regarding appropriate medication cessation, reproductive risks, and contraception information (PMID: 24418289, 26510694).
  • Early treatment is beneficial with consideration for statin medications beginning at age 8 to 10 years old and potentially earlier for individuals with HoFH (PMID: 26510694, 24418289).
  • Some children with HoFH may benefit from liver transplantation (PMID: 23461430, 26510694).

Review date: March 2018

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
LDLR NM_000527.4