Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

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Clinical Phenotype Summary: 

The PCSK9 gene (NM_174936.3), which contains 12 coding exons and is located on chromosome 1p32.3, encodes proprotein convertase subtilisin/kexin type 9. Pathogenic variants in this gene are known to cause PCSK9-related familial hypercholesterolemia (FH), which is inherited in an autosomal dominant fashion. 

Diagnostic criteria for FH include:
•    Extreme hypercholesterolemia
•    Premature coronary heart, cerebral, or peripheral vascular disease
•    Tandon xanthomas
•    Corneal arcus
•    Family history of high cholesterol, heart disease, and/or tendon xanthomas

Heterozygous familial hypercholesterolemia (HeFH) is defined as untreated LDL-C levels >190 mg/dL (>4.9 mmol/L) or untreated total cholesterol levels >310 mg/dL (>8 mmol/L) in adults, and untreated LDL-C levels >160 mg/dL (>4 mmol/L) or untreated total cholesterol levels >230 mg/dL (>6 mmol/L) in children and adolescents. 

Homozygous familial hypercholesterolemia (HoFH) has an earlier age of onset with more severe presentation, with clinical diagnostic criteria that include two pathogenic alleles (in the same or different FH genes), untreated LDL-C levels >500mg/dL (13 mmol/L), treated LDL-C levels >300 mg/dL (>8 mmol/L), cutaneous or tendon xanthoma prior to 10 years of age, and both parents with elevated cholesterol consistent with FH. 

Pathogenic PCSK9 variants are estimated to account for <1% of patients with FH. Treatment options include cholesterol-lowering statins, ezetimibe, bile acid binding resins, and lipoprotein apheresis. Gain of function has been reported as the mechanism of disease for PCSK9-related familial hypercholesterolemia. 

Unique Considerations: 

Loss of function PCSK9 variants have been associated with lower blood cholesterol levels and a reduced risk for developing coronary artery disease.

Clinical Resources: 

Understanding your Positive Familial Hypercholesterolemia Genetic Test Result

Citations: 
•    Hopkins PN et al. Circ Cardiovasc Genet. 2015 Dec;8:823-31 PMID: 26374825
•    Ison H et al. GeneReviews. 2014 Jan 2 [Updated 2022 Jul 7] PMID: 24404629
•    Abifadel M et al. J Intern Med. 2023 Feb;293:144-165 PMID: 36196022
•    Bao X et al. Signal Transduct Target Ther. 2024 Jan 8;9(1):13 PMID: 38185721

Ambry Genetics Gene-Disease Validity Scheme

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. 

To learn more about the ACMG Secondary Findings list, click here.