Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.0.0
• GENE/GENE PANEL: LDLR, APOB, PCSK9
• Condition: Heterozygous Familial Hypercholesterolemia
• Mode(s) of Inheritance: Autosomal Codominant

Actionability Assertion

• LDLR ⇔ 143890: Assertion Pending
• APOB ⇔ 143890: Assertion Pending
• PCSK9 ⇔ 603776: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
High cholesterol / Statins	2	3C	3A	3	11CA

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated as 1/200 to 1/300. [1, 2, 3]

Clinical Features

HeFH is characterized by elevated levels of plasma low-density lipoprotein cholesterol (LDL-C), increased risk of premature cardiovascular disease (CVD), and tendon xanthomas. Untreated, LDL-C concentrations are typically in the range of 190-350 mg/dL. CVD includes both coronary heart disease (CHD) and stroke, though CHD is the more common CVD while stroke occurs rarely. Presentation of CHD may include angina pectoris, myocardial infarction, and peripheral vascular disease. Corneal arcus is also common. [1, 2, 3, 4, 5, 6]

Natural History

In HeFH, a raised LDL-C concentration is present during childhood and may lead to early development of atherosclerosis and CHD, even in the absence of other risk factors for coronary disease. Untreated males have a 50% risk of CHD by age 50 with onset typically in their 30s and 40s while untreated women have at least a 30% risk by the age of 60 with onset typically in their 40s and 50s. HeFH patients with tendon xanthomas have higher risk of CVD compared to FH patients without xanthomas. [1, 2, 3, 4, 5, 6]

2. How effective are interventions for preventing harm?

Patient Management

Patients should consider lifelong, high-intensity statin therapy beginning in children aged 8 or older, although it may be administered to younger patients in special cases. (Tier 1) [2, 4]

These recommendations have been confirmed in more recent guidelines which base recommendations on elevated cholesterol levels without regard to specific etiology such as FH. (Tier 5) [7]

In a study of 2146 patients with FH, patients taking statins were shown to reduce their risk of coronary heart disease by 76% compared to untreated patients. (Tier 5) [8]

Patients should consider taking daily aspirin or other proven similarly effective drug if aspirin is contraindicated. Among patients with a history of atherosclerotic disease, aspirin has been shown to reduce all-cause mortality by 18%, number of strokes by 20%, myocardial infarctions by 30%, and other vascular events by 30%. Among patients without a history of atherosclerotic disease, aspirin has been shown to reduce the risk of myocardial infarction by 30%. However, evidence of effectiveness of aspirin in patients with FH was not provided. (Tier 1) [4]

High blood pressure and diabetes are additional risk factors for CHD and should be treated aggressively. (Tier 2) [1, 9]

Surveillance

A baseline electrocardiogram should be considered (Tier 2) [2]

Lipid levels should be measured every 12 months. (Tier 2) [9]

Blood pressure should be monitored every 6 to 12 weeks. (Tier 2) [9]

Circumstances to Avoid

Patients should avoid additional risk factors for CHD, including smoking, physical inactivity, diets high in saturated fats and cholesterol, unhealthy body weight, and excessive alcohol consumption. (Tier 2) [1, 2]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Codominant

Prevalence of Genetic Variants

Genetic mutations associated with HeFH have been estimated in Dutch population as 1/137-1/244. (Tier 5) [10, 11]

Penetrance

Males have a 50% risk of CHD by age 50 while women have a 30% risk by the age of 60. (Tier 3) [3]

Locus and allele specific penetrance varies for elevated LDL-C levels. High penetrance, up to 90%, has been noted for patients heterozygous with mutations in LDLR and incomplete penetrance for patients heterozygous for mutations in APOB. The penetrance associated with most mutations in PCSK9 is unclear, though patients heterozygous for the Ser127Arg variant have 90% penetrance and patients heterozygous for the Asp374Tyr variant have high penetrance. (Tier 3) [3]

Relative Risk

Information on relative risk associated with HeFH was unavailable.

Expressivity

Expression is variable, with some individuals with HeFH having no detectable signs of disease. (Tier 4) [3]

4. What is the Nature of the Intervention?

Nature of Intervention

The identified action items for this disorder include surveillance (echocardiogram), clinical monitoring (blood pressure and lipid levels) and medication use (statins and aspirin), which are likely associated with mild to moderate risk and burden.

5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?

Chance to Escape Clinical Detection

HeFH is associated with early onset elevated cholesterol levels and CHD, which are not typically screened for in younger adult populations, thus this disorder would likely escape clinical detection given typical clinical care. (Tier 3) [3]

Date of Search: 04.14.2015

Reference List

1. Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. (2011) 5(3 Suppl):S1-8.

2. Identification and management of familial hypercholesterolaemia. NICE. (2008) Website: https://www.nice.org.uk/guidance/cg71

3. E Youngblom, JW Knowles. Familial Hypercholesterolemia. 2014 Jan 02. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174884

4. Risk estimation and the prevention of cardiovascular disease. A national clinical guideline. Edinburgh (Scotland) Scottish Intercollegiate Guidelines Network. SIGN. (2007) Website: http://www.sign.ac.uk/guidelines/fulltext/97/

5. Oosterveer DM, Versmissen J, Yazdanpanah M, Hamza TH, Sijbrands EJ. Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: a systematic review and meta-analysis. Atherosclerosis. (2009) 207(2):311-7.

6. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. Circulation. (2002) 106(25):3143-421.

7. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. (2013) Website: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

8. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JJ, Sijbrands EJ. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. (2008) 337:a2423.

9. Prevention of vascular and metabolic disease. Guidelines for preventive activities in general practice, 8th edition. NCG. (2012) Website: http://www.guideline.gov/content.aspx?id=43854

10. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. (2012) 97(11):3956-64.

11. Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, Sijbrands EJ, Roeters van Lennep JE, Stalenhoef AF, Wiegman A, de Graaf J, Fouchier SW, Kastelein JJ, Hovingh GK. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. (2015) 36(9):560-5.