Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released Status (Pediatric): Passed (Consensus scoring is Complete) P

Condition: Homozygous Familial Hypercholesterolemia
Mode(s) of Inheritance: Autosomal Codominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
LDLR0007750 (hypercholesterolemia, familial, 1)
Strong Actionability
APOB0007751 (hypercholesterolemia, autosomal dominant, type b)
Strong Actionability
PCSK90011369 (hypercholesterolemia, autosomal dominant, 3)
Strong Actionability
Actionability Rationale
There was a final assertion of strong. However, some scorers were concerned about the lack of significant natural history and effectiveness data in previously undetected adults.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Clinical cardiovascular events / Lipid lowering therapy (including apheresis) to FH appropriate LDL-C goal

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The frequency of homozygous familial hypercholesterolemia (HoFH) has historically been estimated to be 1/1,000,000, though genetically isolated subpopulations have higher rates from 1/30,000 to 1/100,000. Recent estimates from general population studies are 1/160,000 to 1/300,000.
1 2 3 4 5 6 7 8 9 10 11 12
Clinical Features
(Signs / symptoms)
The clinical features of HoFH are characterized by extensive xanthomas, premature and progressive cardiovascular disease (CVD), and total cholesterol >500 mg/dL. The major clinical manifestations of FH result from prolonged exposure to high levels of LDL-C leading to the development of atherosclerotic lesions in the heart, brain, and peripheral arteries. Aggressive atherosclerosis of the aortic root occurs, primarily affecting the aortic valve and supravalvular region. Atherosclerosis leads to an increased risk of cardiovascular disease (CVD), most commonly coronary artery disease (CAD). CAD may manifest as symptoms of ischemia (e.g., angina) due the restriction of blood flow; however acute complications such as myocardial infarction (MI) and sudden cardiac death can occur as the first manifestations. Dyspnea, diastolic and systolic left ventricle heart failure, and severe aortic stenosis are common. Xanthomas around the tendons and interdigital folds may occur leading to tendinitis and joint pain.
2 3 5 13 7 8 10 14 15
Natural History
(Important subgroups & survival / recovery)
HoFH commonly presents as physical manifestations in infancy and early childhood, consisting primarily of fleshy cutaneous and tendinous xanthomata, most marked in the Achilles tendon. Clinical CVD events begin as early as the first decade of life, but usually manifest by the second decade, consisting primarily of coronary ostial stenoses and occlusions, aortic valve thickening with stenosis and/or regurgitation, and extensive atherosclerosis of the aortic root. Untreated, most individuals with HoFH develop severe CAD and aortic stenosis before age 20 and die before age 30. Children as young as 4 years of age have suffered sudden death due to acute MI. The rate of either death or coronary bypass surgery by the teenage years is high. HoFH patients who are LDLR-defective (2-25% residual enzyme activity) have a better prognosis than those who are receptor negative (<2% enzyme activity).
2 3 4 16 5 6 13 7 8 9 10 11
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making when pathogenic variant(s) in APOB, LDLR, and/or PCSK9 are identified as a secondary finding:
Patients should be urgently referred to specialized care at the time of diagnosis and have a complete cardiovascular evaluation, as fatal coronary artery occlusions have been reported before 2 years of age. (Tier 1)
2 10
Conventional risk factors for atherosclerotic CVD (ASCVD) such as age, sex, HDL-C, hypertension, smoking, lipoprotein(a), and diabetes should be ascertained in patients with FH. Existing risk calculators for the general population (Framingham Risk Score, Pooled Cohort Equation, European SCORE) may underestimate the risk in patients with FH. If adult patients with FH require further stratification of their ASCVD risk, the Montreal-FH-SCORE (MFHS) may be used, which was developed to stratify risk in FH and is based on age, HDL-C, gender, hypertension, and smoking status. A validation study of the MFHS in 718 adults with FH indicated that patients with a high score had a significant 8.8-fold (95% CI: 5.8-13.3) increased risk of a CVD event compared to patients with a low score. (Tier 1)
Treatment for HoFH should be undertaken within a lipid specialist center. Children with HoFH should be managed by a medical care team (pediatricians specializing in diabetes and/or endocrinology, lipid specialists, geneticists, dieticians, and psychologists) with expertise in FH in an appropriate child-focused setting. (Tier 2)
2 3 4 6 10 17 18 19 20 21
A personalized pharmacologic treatment plan considering age, additional cardiovascular risk factors, psychosocial and socioeconomic factors, and personal as well as family preferences, should be developed as a shared decision process. (Tier 1)
2 19
The initial treatment for individuals with FH, irrespective of their calculated cardiovascular risk, should be a high intensity statin. Statin therapy is recommended to be initiated by 8-12 years of age; however, HoFH patients under the age of 8-10 years with high-risk family history, high-risk conditions, or multiple risk factors might be considered for medication initiation at a younger age. Target serum LDL-C concentrations have not been established for children, but in adults, the goal should be a reduction of at least 50% in LDL-C concentration from baseline. Statin treatment is lifelong. A meta-analysis of 6 studies (669 children with HeFH) estimated that statins lowered LDL-C by an additional 32.2% (95% CI: 29.4-34.9%) over placebo at 48-week follow-up. No studies have reported the impact of statins vs placebo on clinical outcomes in adults with FH. However, high and moderate quality RCTs from adult populations without FH have found that high-intensity statins reduce non-fatal MI (relative risk [RR]: 0.46, 95% CI: 0.37-0.59). Statins have also been shown to have a small (but non-clinically important) effect on reducing 5-year all-cause mortality (RR: 0.90, 95% CI: 0.80-1.00), CV mortality (RR: 0.73, 95% CI: 0.61-0.88), and stroke (RR: 0.80, 95% CI: 0.70-0.91). (Tier 1)
Based on a meta-analysis of 4 retrospective observational studies, individuals with HeFH of all ages in the pre-statin era (defined as before 1987) exhibited a higher risk for stroke compared with the general population (2 studies of 629 patients with HeFH; OR: 7.66, 95% CI: 6.06-9.68) but a lower odds for stroke following the generalization of statin therapy (2 studies of 2745 patients with HeFH; OR: 0.25, 95% CI: 0.18-0.36). (Tier 1)
Ezetimibe, as a monotherapy or in combination with statin therapy, is recommended as an option for treating HoFH in patients in whom initial statin therapy is contraindicated or not tolerated or when LDL-C levels are not controlled by statins alone. An RCT of 50 children and adults with HoFH showed that ezetimibe plus statin reduced LDL-C levels compared to statin alone (20.7% vs 6.7 % reduction, respectively; p<0.01). An RCT of 248 patients aged 10-17 years with HeFH found that ezetimibe plus simvastatin reduced LDL-C compared to simvastatin alone (49.5% vs 34.4%, respectively; p<0.01). No trials of ezetimibe in individuals with FH have reported on clinical outcomes. In non-FH individuals, an RCT (IMPROVE-IT trial) of 18,144 adult patients with stabilized acute coronary syndrome found a 6.4% relative risk reduction at 6 years for the primary endpoint (a composite of cardiovascular death, major coronary event, or non-fatal stroke) with use of ezetimibe plus simvastatin compared with simvastatin alone (hazard ratio [HR]: 0.94, 95% CI: 0.89-0.99). (Tier 1)
2 19 23
Patients with FH and intolerance or contraindications to statins or ezetimibe should be considered for treatment with either a bile acid sequestrant (resin) or a fibrate. RCTs have found that bile acid sequestrants (6 RCTs, N= 248 adult and N=214 pediatric patients with FH) and fibrates (3 RCTs, N= 208 adult and N=14 pediatric patients with FH) can result in similar reductions in LDL-C and total cholesterol compared to placebo as treatment with statins. (Tier 1)
10 19 23
There is ongoing research on newer pharmacotherapeutic agents including PCSK9 inhibitors (Alirocumab and Evolocumab), MTP inhibitors (lomitapide) and antisense oligonucleotides (mipomersen) and their role as primary therapies patients with HoFH.
LDL-C apheresis should be offered for treatment of HoFH with initiation based on response to lipid-lowering therapy (LLT), the presence of CHD, and child weight (>15kg). For children, treatment can be performed as early as technically feasible (before age 5 and at least by age 8) and must be under the care of lipid specialists in academic medical centers with this expertise. (Tier 1)
2 10 19
A systematic review of 7 pre-post observational studies of apheresis in HoFH (N= 61) found mean reductions in LDL-C levels from 57-76% in patients of all ages. Two of these studies (n=39) reported that after extended follow up, the mean reduction was around 34-36%. Data from 34 adults with FH receiving apheresis for an average of 2.5 years found that after apheresis individuals had a 3.2-fold decrease in CV events and over a 20-fold decrease in cardiovascular interventions. Subjectively, individuals reported decreased episodes of angina and improved quality of life. (Tier 1)
Data from the German Lipoprotein Apheresis Registry, based on over 15,000 apheresis procedures in 1279 both FH and non-FH adults performed through 2015, showed a median acute reduction in LDL-cholesterol of 69% in hyperlipidemic patients with CVD and a 97% decrease in the incidence of major adverse coronary events during the first year of lipoprotein apheresis compared with the 2 years preceding the start of this treatment. In addition, a French study of 20 children with HoFH showed that the frequency of aortic stenosis and need for surgery were associated with the age at which lipoprotein apheresis was initiated, where those with aortic root atheroma started apheresis at age 10 whereas those without atheroma had started it earlier, at age 5. (Tier 5)
Daily oral aspirin may be considered to prevent atherothrombosis in asymptomatic adults and adolescents aged 16 and older. In pediatric patients, aspirin may be considered with caution. No studies of aspirin in FH were identified. In patients with HoFH who have not had a cardiovascular event, a net benefit of aspirin is a reasonable assumption because atheromatous disease is inevitable. (Tier 2)
3 6 7 33
An analysis of 6 primary prevention trials of non-FH individuals of low average vascular disease risk found aspirin, compared to placebo, reduced serious vascular events (RR: 0.88, 95% CI: 0.82-0.94), due mainly to a reduction in non-fatal MI (RR: 0.77, 95% CI: 0·67–0·89); the effect on stroke and mortality were not significant. Analysis of 16 secondary prevention trials of non-FH individuals of high average vascular disease risk found aspirin yielded a greater absolute reduction in serious vascular events (RR: 0.81, 95% CI: 0.75-0.87), stroke (RR: 0.81, 95% CI: 0.71-0.92), major coronary events (RR: 0.80, 95% CI: 0.73-0.88), and total mortality (RR: 0.90, 95% CI: 0.82-0.99). (Tier 2)
Lifestyle advice should be provided as a component of medical management, and not a substitute for LLT, including: individualized nutritional advice and physical activity advice, limiting alcohol consumption, stress reduction, and support for weight loss and decreases in blood pressure and glucose levels in line with national guidance for the general population. The aim of these interventions is not to lower LDL-C, but to confer a cardioprotective effect. However, there is no evidence that these interventions improve clinical outcomes in patients with FH. (Tier 2)
Dietary modifications may be started after 2 years of age and should be under the supervision of a dietician or nutritionist for children and young adults. Foods containing plant stanols and sterols may be added to the diet but must be taken consistently to be effective. A systematic review (6 RCTs, N=124 HeFH patients) as well as 3 additional RCTs (ranging from 18-42 FH patients of all ages, 4-12 weeks follow-up) found significant reductions in LDL-C of 0.48-0.69 mmol/l (9.2-10.2%) in both children and adults with FH consuming plant sterol and stanol enriched foods. (Tier 2)
Patients should be taught “red flag” symptoms of CVD and acute coronary events. (Tier 2)
Psychological support (including family support) should be part of routine care. (Tier 2)
The lipid team should be involved if a patient is hospitalized. An alert card with contact details should be issued. (Tier 2)
Non-hormonal contraceptive techniques are recommended. If essential, oral contraceptives with the lowest thrombotic risk should be selected. (Tier 2)
3 6
Women should be advised that pregnancy in HoFH is hazardous due to the aggravation of hypercholesterolemia due to discontinuation of pharmacotherapy coupled with the effects of high levels of estrogen and progesterone on lipoprotein metabolism. Pre-conception counseling and shared-care arrangements should include expertise in cardiology, lipidology and obstetrics. Pre-conception, women should be referred to a cardiologist for a detailed cardiovascular assessment, including the aortic valve and root, and evaluation of arteriosclerosis status. (Tier 2)
If HRT is provided for relief of postmenopausal symptoms, it should be taken in the form of parenteral preparations, which have the lowest thrombotic risk. (Tier 2)
All people with FH should be offered a regularly structured review that is carried out every 6-12 months including an update of family pedigree, changes in CHD status of relatives, assessment of any symptoms of CHD, smoking status, fasting lipid profile, discussion about concordance with medication, possible side effects of treatment, and changes in lifestyle or LLT that may be required. Children should also be assessed for weight, growth, and developmental milestones. (Tier 2)
6 9 19 14 33
Frequent surveillance with cardiovascular imaging and stress testing is necessary to detect and monitor progression of atherosclerosis and valvular diseases, which may progress even when cholesterol levels are reduced. Evaluations should include a patient interview and physical examination; a medical questionnaire and imaging to evaluate coronary and peripheral artery disease (CAD and PAD; especially the carotid), aortic stenosis, aortic aneurisms, and valvular disorders. In children, non-invasive imaging is preferable. For adults, evaluations should be repeated every 6 months with subsequent Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years or more frequently if needed. For children with HoFH, frequency of evaluations should be based on the age of the child, disease severity, and presence of CVD risk factors. (Tier 2)
2 3 6 34 35 37 9 10 19 20 21
Circumstances to Avoid
Individuals with FH should be strongly discouraged from smoking or advised to stop smoking given the greatly increased risk for CHD. In patients with FH, LDL-C catabolism is slow and LDL-C is susceptible to oxidization. In smokers, children and adults with FH and CAD flow mediated dilatation was reduced or absent (p<0.001) compared to controls. (Tier 2)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Codominant
Prevalence of Genetic Variants
Population screening of 50,762 individuals in a US health care system identified pathogenic variants associated with FH in 1:256 in unselected individuals; however, this may be an overestimate as it was based on screening within a single health care delivery system. None of these cases were homozygous of compound heterozygous for pathogenic variants. (Tier 3)
(Include any high risk racial or ethnic subgroups)
In a case series of 17 patients with HoFH, magnetic resonance imaging of the aortic root identified atherosclerotic plaques in 53% of patients and supravalvular aortic stenosis in 41%. (Tier 3)
An analysis of individuals identified from cascade screening identified 49 patients with HoFH (20 were true homozygous, 25 were compound heterozygous). Within this population, 50% of the patients met the clinical criteria for HoFH (LDL-C > 13.0 mmol/L) and 29% had a recorded history of a CVD event. (Tier 5)
About 79% of the pathogenic variants in the LDLR gene are likely expressed as a hypercholesterolemic phenotype. (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information related to relative risk was identified related to HoFH.
There is a wide variation in age of onset and speed of progression in CAD among FH patients. (Tier 3)
Individuals with FH develop aortic calcifications in a gene-dosage and age-dependent manner. (Tier 3)
In FH, the expression of ischemic heart disease remains variable, ranging from severe premature disease in up to 10% of affected individuals by 40 years of age to the absence of cardiovascular disease until late in life in a similarly small percentage. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions for HoFH include biochemical surveillance, invasive and non-invasive cardiac imaging, medication use, and apheresis. Statins are generally well-tolerated. Adverse effects are rare even at standard doses, but include elevated liver enzymes, muscle symptoms (the most severe of which is rhabdomyolysis, which can be fatal), new onset diabetes, potential fetal teratogenicity, and impacts on sexual and physical maturation. A recent systematic review and meta-analysis of statin therapy in almost 800 children with FH did not find any statistically significant differences between statin- and placebo-treated children for the occurrence of adverse events, sexual development, muscle toxicity, or liver toxicity. There was a minimal difference in growth in favor of the statin group. Apheresis typically needs to be undertaken approximately every two weeks (though frequency can vary) and requires invasive and/or long-term vascular access, specialist administration, likely anticoagulation, and monitoring with the duration of the procedure ranging from 2 to >3 hours. Serious adverse events are rare, with the most common reactions being light-headedness, nausea/vomiting, hypotension, and chest pain. Because of the demands of apheresis, psychological status and quality of life should be monitored in all patients. Adverse reactions with ezetimibe monotherapy are usually mild and transient and include gastrointestinal symptoms (e.g., abdominal pain) and fatigue; when taken with a statin adverse events may include elevated liver enzymes, headache, and myalgia. Aspirin can, in rare cases, lead to gastrointestinal and extracranial bleeds in patients of all ages, and Reye’s syndrome in children. Adverse effects of bile acid sequestrants are gastrointestinal (bloating, nausea, diarrhea, and constipation) which significantly affect compliance; as well as malabsorption of fat-soluble vitamins (A, D, E) and some medications.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Many patients with FH remain unrecognized, particularly in countries that have not enacted a national registry. (Tier 3)
The majority of children and adolescents with FH are undiagnosed, as symptoms and signs only develop after decades of hypercholesterolemia. (Tier 4)
HoFH is typically diagnosed when considerable CAD has already developed. (Tier 3)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
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