FHNext® is a 4-gene panel that analyses genes associated with familial hypercholesterolemia (FH), an inherited disorder characterised by high cholesterol and an increased risk for heart disease.
Why Is This Important?
Knowing if your patient has FH can help you determine their future coronary artery disease risk and guide your medical management recommendations.
Key benefits include:
- Confirm a diagnosis, particularly when clinical criteria are unclear or borderline in an individual
- 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 following1:
- 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 scenarios1:
- 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
1Sturm, Amy C., et al., Clinical Genetic Testing for Familial Hypercholesterolemia. Journal of the American College of Cardiology. 72 (2018) 662-680
The FHNext® test is an analysis of 4 genes associated with familial hypercholesterolemia. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardised 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 and is followed by polymerase chain reaction (PCR) and Next-Generation sequencing. Additional Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Potentially homozygous variants, variants in regions complicated by pseudogene interference, and variant calls not satisfying depth of coverage and variant allele frequency quality thresholds are verified by Sanger sequencing. 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 for all genes using a custom pipeline based on read-depth from NGS data followed by a confirmatory orthogonal method, as needed. Exon-level resolution may not be achieved for every gene.
The FHNext® test is designed and validated to be capable of detecting >99% of described mutations in the genes represented on this test (analytical sensitivity). The clinical sensitivity of the FHNext® test may vary widely according to the specific clinical and family history.
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