FHNext

Familial hypercholesterolemia is an inherited disorder characterized by high cholesterol and an increased risk for heart disease. FHNext is a 4-gene panel that analyzes genes associated with familial hypercholesterolemia, clarifying a diagnosis and allow for individualized disease management and treatment.

Quick Reference
Test Code 8680
Turnaround Time (TAT) 14-21 days
Number of Genes 4

Ordering Options

We now offer single site analysis (SSA) at no additional cost to family members

following single gene or panel testing* of the first family member (proband) within 90 days of the original Ambry report date.

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*excludes Exome and SNP Array tests

Why Is This Important?

Knowing if your patient has Familial Hypercholesterolemia can help you determine their future coronary artery disease risk and guide your medical management recommendations. Key benefits include:

  1. Confirm a diagnosis, particularly when clinical criteria are unclear or borderline in an individual
  2. Help tailor medical treatment, including avoiding/adjusting simvastatin use based on SLCO1B1 genotype
  3. Clarify risks to family members, including the inheritance pattern

When To Consider Testing

  • Genetic testing for FH should be offered to individuals of any age in whom a strong clinical index of suspicion for FH exists. This index of suspicion includes the following:1
    • Children with persistent* LDL-C levels >160 mg/dl without an apparent secondary cause of hypercholesterolemia and with at least 1 first-degree relative similarly affected or with premature CAD or where family history is not available (e.g., adoption)
    • Children with persistent* LDL-C levels >190 mg/dl even in the absence of a positive family history
    • Adults with persistent* LDL-C levels >190 mg/dl without an apparent secondary cause of hypercholesterolemia, and with at least 1 first-degree relative similarly affected or with premature CAD or where family history is not available (e.g., adoption)
    • Adults with persistent* LDL-C levels >250 mg/dl without an apparent secondary cause of hypercholesterolemia, even in the absence of a positive family history
  • Genetic testing for FH may be considered in the following clinical scenarios:1
    • Children with persistent* LDL-C levels >160 mg/dl (without an apparent secondary cause of hypercholesterolemia) with an LDL-C level >190 mg/dl in at least 1 parent or a family history of hypercholesterolemia and premature CAD
    • Adults with no pre-treatment LDL-C levels available but with a personal history of premature CAD and family history of both hypercholesterolemia and premature CAD
    •  Adults with persistent* LDL-C levels >160 mg/dl (without an apparent secondary cause of hypercholesterolemia) in the setting of a family history of hypercholesterolemia and either a personal history or a family history of premature CAD
  • Genetic testing for at-risk family members (cascade testing):1
    • When a patient is identified to have a mutation, genetic testing for the identified variant should be offered to all 1st-degree relatives (i.e. parents, siblings, children)    
    • If 1st-degree relatives are unavailable/ do not wish to undergo testing, testing should be offered to second-degree relatives (i.e. aunts/uncles, grandparents).

*Pre-treatment LDL measurements

Mutation Distribution and Detection Rates

~70% of patients with a diagnosis of FH have a mutation in one of the FHNext genes (clinical sensitivity). FHNext can detect >99.9% of described mutations in the included genes, when present (analytic sensitivity).

Test Description

FHNext includes 4 genes associated with FH: APOB, LDLR, PCSK9, and LDLRAP1. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS. Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.2 This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis is performed using a custom pipeline based on read-depth from NGS data and/or utilizing a targeted chromosomal microarray with confirmatory MLPA when applicable. Analysis of the pharmacogenetic c.521T>C SNP in the SLCO1B1 gene is performed. If Specific Site Analysis is requested, only specific region(s) of DNA is (are) amplified by PCR and sequenced.

 

1. Sturm, Amy C., et al., Clinical Genetic Testing for Familial Hypercholesterolemia. Journal of the American College of Cardiology. 72 (2018) 662-680.

2. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.

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