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 - Under Revision 1.0.1
• GENE/GENE PANEL: LDLR, APOB, PCSK9
• Condition: Homozygous Familial Hypercholesterolemia
• Mode(s) of Inheritance: Autosomal Codominant

Actionability Assertion

• LDLR ⇔ 143890: Assertion Pending
• APOB ⇔ 144010: 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
High cholesterol / LDL apheresis	2	3C	3B	2	10CB

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 homozygous familial hypercholesterolemia (HoFH) has been widely estimated from 1/160,000 to 1/1,000,000. [1, 2, 3, 4, 5]

Clinical Features

HoFH is characterized by extremely elevated levels of plasma low-density lipoprotein cholesterol (LDL-C), significantly increased risk of premature cardiovascular disease (CVD), and tendon xanthomas. Untreated, LDL-C concentrations are typically in the range of 400-1000 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. Tuberous and dermal xanthomas as well as corneal arcus are also common. [2, 6, 7, 3, 1]

Natural History

HoFH is aggressive and, if untreated, patients typically develop CVD during childhood or adolescence and severe vascular disease by their mid-20s. Patients often die in their 20s or earlier. [2, 6, 7, 3, 1]

2. How effective are interventions for preventing harm?

Patient Management

Patients should consider LDL apheresis depending on factors such as the person's response to drug therapy and presence of CHD. Observational studies have shown that treatment with LDL apheresis lowered LDL concentrations by 72% compared to drug therapy. (Tier 2) [2]

Patients should consider lifelong, high-intensity statin therapy beginning as early as possible (recommended to start in children aged 8 or older, although it may be administered to younger patients in special cases). (Tier 1) (Tier 1) [2, 6]

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) [8]

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) [9]

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) [6]

Surveillance

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

Lipid levels should be measured every 12 months. (Tier 2) [10]

Blood pressure should be monitored every 6 to 12 weeks. (Tier 2) [10]

Patients should be monitored with various imaging modalities, including echocardiograms, CT angiograms, and cardiac catheterization. (Tier 3) [3]

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) [2, 1]

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

Mode of Inheritance

Autosomal Codominant

Prevalence of Genetic Variants

The prevalence of homozygous familial hypercholesterolemia (HoFH) has been widely estimated from 1/160,000 to 1/1,000,000. (Tier 3) (Tier 3) [1, 2, 3, 4, 5]

However, the prevalence of carriers of homozygous or compound heterozygous mutations associated with FH has been estimated as 1/300,000 in a Dutch population. (Tier 5) [11]

Penetrance

Penetrance is high, with most patients experiencing severe CHD by their mid-20s. (Tier 3) [3]

Relative Risk

Information on relative risk associated with HoFH was unavailable.

Expressivity

Information on variable expression associated with HoFH was unavailable.

4. What is the Nature of the Intervention?

Nature of Intervention

The identified action items for this disorder included surveillance (echocardiograms, CT angiograms, and cardiac catheterization), medication use (statins and aspirin), and apheresis. This last intervention is a mechanical method of removing LDL-C from the blood and typically needs to be undertaken approximately every two weeks and requires specialist administration and monitoring, which is likely associated with moderate to high risk and/or burden.

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

Chance to Escape Clinical Detection

HoFH is associated with early onset elevated cholesterol levels and CHD; however, the presentation may be so severe that it is unlikely a patient would escape clinical detection into adulthood. (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. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjaerg-Hansen A, Watts GF, Averna M, Boileau C, Boren J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. (2014) 35(32):2146-57.

5. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. (2013) 34(45):3478-90a.

6. Risk estimation and the prevention of cardiovascular disease. A national clinical guideline. SIGN. (2007) Website: http://www.sign.ac.uk/pdf/sign97.pdf

7. 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.

8. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 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. Circulation. (2014) 129(25 Suppl 2):S1-45.

9. 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.

10. Prevention of vascular and metabolic disease. Guidelines for preventive activities in general practice, 8th edition.East Melbourne (Australia). Other. (2012) Website: http://www.nmml.org.au/content/Document/RACGP%20Red%20Book.pdf

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.