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Test Code ADHP Familial Hypercholesterolemia/Autosomal Dominant Hypercholesterolemia Genetic Testing Reflex Panel

Reporting Name

FH/ADH Genetic Reflex Panel

Useful For

Aiding in the diagnosis of familial hypercholesterolemia defective apoB-100 in individuals with elevated, untreated low-density lipoprotein cholesterol concentrations


Distinguishing the diagnosis of autosomal dominant hypercholesterolemia from other causes of hyperlipidemia, such as familial combined hyperlipidemia


Genetic evaluation of hypercholesterolemia utilizing a cost-effective, reflex-testing approach

Profile Information

Test ID Reporting Name Available Separately Always Performed
ADHI FH/ADH Genetic Interpretation No Yes
APOBP APOB Genotype No Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
LDLMP LDLR Large Del/Dup Yes, (order LDLM) No
LDLSP LDLR, Full Gene Sequence Yes, (order LDLRS) No

Testing Algorithm

If APOB genotype is negative, LDLSP / Familial Hypercholesterolemia, LDLR Full Gene Sequencing will be performed at an additional charge.


If LDLR full gene sequence is negative, LDLMP / Familial Hypercholesterolemia, LDLR Large Deletion/Duplication, Molecular Analysis will be performed at an additional charge.


See Familial/Autosomal Dominant Hypercholesterolemia Diagnostic Algorithm in Special Instructions.

Method Name

APOBP: Polymerase Chain Reaction (PCR) with Allele-Specific Primer Extension (ASPE)

Performing Laboratory

Mayo Medical Laboratories in Rochester

Specimen Type

Whole Blood EDTA

Additional Testing Requirements

Multiple cardiovascular-related gene sequencing tests can be performed on a single specimen after a single extraction. See Multiple Cardiovascular-Related Gene Sequencing Tests in Special Instructions for a list of tests that can be ordered together.

Necessary Information

Include physician's name and phone number with the specimen.

Specimen Required

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.

Specimen Minimum Volume

0.5 mL

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood EDTA Ambient (preferred)

Reject Due To









Reference Values

An interpretive report will be provided.

Day(s) and Time(s) Performed


CPT Code Information

81401-APOB gene

81479-LDLR gene (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
ADHP FH/ADH Genetic Reflex Panel 56752-9


Result ID Test Result Name Result LOINC Value
29283 APOB Genotype (Result) 73748-6
29282 FH/ADH Genetic Interpretation 69047-9
29286 Reviewed By No LOINC Needed

Analytic Time

14 days

Method Description

Direct variant analysis for APOB R3500W and R3500Q is performed following PCR amplification and allele-specific, single-base primer extension. If the sample is positive, testing stops and a report is issued. If the sample is negative for a variant, then LDLR full gene sequencing is performed. All 18 exons, splice junctions, and a portion of the promoter and 3' untranslated region (UTR) of the LDLR gene are amplified by PCR and then subjected to direct bidirectional DNA sequence analysis. If the sample is positive for an LDLR sequencing variant, testing is stopped and a report is issued. If the sample is variant negative by LDLR sequencing, then LDLR large deletion/duplication analysis is performed. Multiplex ligation-dependent probe amplification (a PCR-based method) is utilized.(Unpublished Mayo methods)


Blood samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.


Absence of a variant does not preclude the diagnosis of autosomal dominant hypercholesterolemia unless a specific variant has been previously identified in an affected family member.


The APOB genotyping component of this test only detects the R3500W and R3500Q variants; other APOB variants are not detected.


The LDLR sequencing method will not detect LDLR variants that occur in the introns (except in the splicing regions) and regulatory regions (except the sterol-regulated portion of the promoter) of the gene.


Sometimes a genetic alteration of unknown significance may be identified. In this case, testing of family members may be useful to determine pathogenicity of the alteration.


In addition to disease-related probes, the multiplex ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.

Specimen Retention Time

2 months (extracted DNA only is saved)

Clinical Information

Autosomal dominant hypercholesterolemia (ADH) is characterized by high levels of low-density lipoprotein (LDL) cholesterol, and associated with premature cardiovascular disease and myocardial infarction. Approximately 1 in 500 individuals worldwide are affected by ADH. Most ADH is caused by genetic variants leading to decreased intracellular uptake of cholesterol. The majority of these cases have familial hypercholesterolemia (FH), which is due to variants in the LDLR gene, which encodes for the LDL receptor. Approximately 15% of ADH cases have familial defective apolipoprotein B-100 (FDB) due to variants in the LDL receptor-binding domain of the APOB gene, which encodes for apolipoprotein B-100.


ADH can occur in either the heterozygous or homozygous state, with 1 or 2 variant alleles, respectively. In general, FH heterozygotes have 2-fold elevations in plasma cholesterol and develop coronary atherosclerosis after the age of 30. Homozygous FH individuals have severe hypercholesterolemia (generally greater than 650 mg/dL) with the presence of cutaneous xanthomas prior to 4 years of age, childhood coronary heart disease, and death from myocardial infarction prior to 20 years of age. Heterozygous FH is prevalent among many different populations, with an approximate average worldwide incidence of 1 in 500 individuals, but as high as 1 in 67 to 1 in 100 individuals in some South African populations and 1 in 270 in the French Canadian population. Homozygous FH occurs at a frequency of approximately 1 in 1,000,000. Similar to FH, FDB homozygotes express more severe disease, although not nearly as severe as FH homozygotes. Approximately 40% of males and 20% of females with an APOB variant will develop coronary artery disease. In general, when compared to FH, individuals with FDB have less severe hypercholesterolemia, fewer occurrences of tendinous xanthoma, and a lower incidence of coronary artery disease. Plasma LDL cholesterol levels in patients with homozygous FDB are similar to levels found in patients with heterozygous (rather than homozygous) FH.


The LDLR gene maps to chromosome 19p13 and consists of 18 exons spanning 45 kb. Hundreds of variants have been identified in the LDLR gene, the majority of them occurring in the ligand binding and epidermal growth factor (EGF) precursor homology regions in the 5' region of the gene. The majority of variants in the LDLR gene are missense, small insertion or deletion variants, and other point variants, most of which are detected by full gene sequencing. Approximately 10% to 15% of variants in the LDLR gene are large rearrangements, such as large exonic deletions and duplications.


The APOB gene maps to chromosome 2p. The vast majority of FDB cases are caused by a single APOB variant at residue 3500, resulting in a glutamine substitution for the arginine residue (R3500Q). This common FDB variant occurs at an estimated frequency of 1 in 500 individuals of European descent. A less frequently occurring variant at that same codon, which results in a tryptophan substitution (R3500W), is more prevalent in individuals of Chinese and Malay descent, and has been identified in the Scottish population as well. The R3500W variant is estimated to occur in approximately 2% of ADH cases. Residue 3500 interacts with other apolipoprotein B-100 residues to induce conformational changes necessary for apolipoprotein B-100 binding to the LDL receptor. Thus, variants at residue 3500 lead to a reduced binding affinity of LDL for its receptor.


Identification of 1 or more variants in individuals suspected of having ADH helps to determine appropriate treatment of this disease. Treatment is aimed at lowering plasma LDL levels and increasing LDL receptor activity. FH heterozygotes and FDB homozygotes and heterozygotes are often treated with 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (ie, statins), either in monotherapy or in combination with other drugs such as nicotinic acid and inhibitors of intestinal cholesterol absorption. Such drugs are generally not effective in FH homozygotes, and treatment in these individuals may consist of LDL apheresis, portacaval anastomosis, and liver transplantation. Screening of at-risk family members allows for effective primary prevention by instituting statin therapy and dietary modifications at an early stage.


This test provides a reflex approach to diagnosing the above disorders. The tests can also be separately ordered:

-LDLRS / Familial Hypercholesterolemia, LDLR Full Gene Sequencing

-LDLM / Familial Hypercholesterolemia, LDLR Large Deletion/Duplication, Molecular Analysis


See Familial/Autosomal Dominant Hypercholesterolemia Diagnostic Algorithm in Special Instructions.


An interpretive report will be provided.


1. Familial/Autosomal Dominant Hypercholesterolemia Patient Information (T637) is required in Special Instructions

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

3. If not ordering electronically, complete, print, and send a Cardiovascular Test Request Form (T724) with the specimen (