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 3.0.4 Status (Pediatric): Passed (Consensus scoring is Complete) P

Condition: Heterozygous Familial Hypercholesterolemia
Mode(s) of Inheritance: Semidominant inheritance
Actionability Assertion
Gene Condition Pairs(s)
Final Assertion
LDLR0007750 (hypercholesterolemia, familial, 1)
Definitive Actionability
APOB0007751 (hypercholesterolemia, autosomal dominant, type b)
Definitive Actionability
PCSK90011369 (hypercholesterolemia, autosomal dominant, 3)
Definitive Actionability
Actionability Rationale
The evidence meets the working criteria for a definitive assertion: (1) the penetrance evidence is from an unselected population; (2) although we extrapolated from a general population that shows statins reduce the outcome of non-fatal myocardial infarction, there was also data from HeFH individuals that showed a reduction in stroke risk from statin therapy; and (3) the effectiveness evidence is based on a direct impact of intervention on the outcome. This topic has been assigned as assertion of definitive. Thus, this topic will not be updated unless it is renominated because of new evidence which could change the assertion.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Clinical cardiovascular events / Lipid lowering therapy 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 Condition
The prevalence of heterozygous familial hypercholesterolemia (HeFH) is most commonly estimated at 1:200-500, though estimates from 1/67 to 1/1000 have been reported, with higher prevalence being reported in certain ethnic groups (e.g., French Canadians, South Africans, Lebanese). Studies in unselected general populations estimate the prevalence of HeFH based on current diagnostic criteria (combination of genetic and clinical findings) as 1/200 and, for molecularly defined HeFH, 1/244. HeFH has been estimated to affect between 14 and 34 million individuals worldwide.
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Clinical Features
(Signs / symptoms)
HeFH is associated with a lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) with levels generally 350-550 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. This 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 to restriction of blood flow; however, acute complications such as myocardial infarction (MI) and sudden cardiac death can occur as the first manifestations. Stroke occurs more rarely. Other manifestations may include corneal arcus and xanthomas (cholesterol deposits), which can occur around the eyelids and within tendons of the elbows, hands, knees, and feet.
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Natural History
(Important subgroups & survival / recovery)
Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. HeFH patients with tendon xanthomas have higher risk of CVD compared to FH patients without xanthomas (odds ratio [OR]: 3.20, 95% CI: 2.12-4.82).
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:
Conventional risk factors for atherosclerotic cardiovascular disease (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, HCL-C, gender, hypertension, and smoking status. A validation study of 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)
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)
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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 as early as 8-12 years of 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 an additional 32.2% (95% CI: 29.4-34.9%) over placebo at 48-week follow-up. No studies have examined 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 (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 HeFH 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 248 patients aged 10-17 years with HeFH showed that ezetimibe plus simvastatin reduced LDL-C compared to simvastatin alone (49.5% vs 34.4%, respectively; p<0.01). 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). However, no trials of ezetimibe in individuals with FH have been published for clinical outcomes. In non-FH individuals, an RCT (IMPROVE-IT trial) of ezetimibe plus simvastatin vs simvastatin alone in 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 (HR: 0.94; 95%; CI: 0.89-0.99). (Tier 1)
A retrospective analysis of 258 adults with genetically confirmed HeFH on lipid lowering therapies (42% on statins alone, 43% on statins plus ezetimibe, and 13% on statins, ezetimibe, and a PCSK9 inhibitor) found that LDL-C levels were directly associated with ASCVD events during follow-up (median 13 years). The expected ASCVD-free cumulative survival was 34.8 years from the start of lipid lowering therapies for patients in the lowest LDL-C quartile compared to 25.7 years for those in the highest quartile (p=0.001), and a progressively higher frequency of follow-up ASCVD events as the LDL-C burden ranked quartiles increased (p < 0.001). In addition, beginning LLT earlier protected against follow-up ASCVD events. (Tier 5)
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 results in similar reductions in LDL-C and total cholesterol compared to placebo as treatment with statins. (Tier 1)
PCSK9 inhibitors, as a monotherapy or in combination with statins and/or ezetimibe, may be considered in HeFH, particularly in patients for whom a statin is contraindicated or when LDL-C is not controlled with statin monotherapy or statin/ezetimibe combination therapy. (Tier 1)
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A pooled analysis of 8 RCTs of patients with FH (1826 with HeFH, 49 with HoFH) on statin with or without other lipid-lowering therapies (LLTs) found that, compared with placebo, PCSK9 antibody therapy reduced mean LDL-C levels by 48.5% (95% CI: 43.9-53.2%; p<0.001) at up to 24 weeks. Stratified by FH type, LDL-C was reduced in HeFH by 51.0% (95% CI: 46.5-55.6%; p<0.0001) and in HoFH by 31.0% (95% CI: 28.0-34.0%; p<0.0001). (Tier 1)
A meta-analysis of 35 RCTs comprising 45,539 adults (predominantly non-FH; mean follow-up of 85.5 weeks) on statins found that, compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of MI (2.3% vs 3.6%, OR: 0.72; 95% CI: 0.64–0.81), stroke (1.0% vs 1.4%; OR: 0.80; 95% CI: 0.67–0.96), and coronary revascularization (4.2% vs 5.8%, OR: 0.78; 95% CI: 0.71–0.86). No significant change was observed in all-cause or cardiovascular mortality. Although studies of patients with FH were not analyzed separately, cardiovascular endpoints were not significantly different in studies of FH patients (8 RCTS comprised of 1391 HeFH and 49 HoFH) compared to studies that included non-FH patients. (Tier 1)
Rare antidrug antibodies have been reported in those treated with PCSK9 inhibitors, but their impact on long-term treatment effectiveness has not been determined. (Tier 2)
Healthcare professionals should offer adults with FH a referral to specialists with expertise in FH and cardiology if assessed to be at very high risk of a coronary event based on established or suspected CHD, family history of premature CHD, or two or more other CV risk factors. Ideally, children with FH should be managed by a medical care team (pediatricians specializing in diabetes and/or endocrinology, lipid specialists, geneticists, dieticians, cardiologists, and psychologists) with expertise in FH in a child-focused setting. (Tier 2)
A complete cardiological investigation, including a baseline electrocardiogram (ECG), is indicated at the time of presentation, since CVD may already be present. (Tier 1)
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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) and three additional small 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)
Pre-conception counseling and shared care arrangements, to include expertise in cardiology, lipidology and obstetrics, should be made for women with FH who are considering pregnancy or are pregnant, including assessment of CHD risk particularly to exclude aortic stenosis. (Tier 2)
All people with FH should be offered a regularly structured review that is carried out at least annually 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)
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Circumstances to Avoid
Individuals with FH should be strongly discouraged from smoking or advised to stop smoking given the greatly increased risk for CHD and PAD. 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 much reduced or absent (p<0.001) compared to controls. (Tier 2)
Isotretinoins, which are used for the treatment of acne, should be avoided in untreated patients with HeFH as they increase thromboembolic and cardiovascular risk. (Tier 2)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Semidominant inheritance
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. (Tier 3)
In most studies, the frequency of detectable pathogenic variants in patients with a clinically definite or probable HeFH is between 40-80%. (Tier 3)
1 5
(Include any high risk racial or ethnic subgroups)
Based on studies of individuals selected based on clinical criteria in the pre-statin era, untreated males are at 50% risk for a fatal or non-fatal coronary event by age 50 years, and women are at 30% risk by 60 years. (Tier 3)
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Seventy nine percent of the pathogenic variants in the LDLR gene are likely expressed as a hypercholesterolemic phenotype. (Tier 3)
Incomplete penetrance is noted for those heterozygous for a APOB pathogenic variant. (Tier 3)
Recent findings suggest that only 73% of those with a heterozygous LDLR pathogenic variant have an LDL level >130 mg/dL, suggesting lower penetrance than previously proposed. (Tier 3)
While penetrance up to 90% is noted for some pathogenic variants in PCSK9, the penetrance for other PCSK9 pathogenic variants remains largely unknown. (Tier 3)
In a US health care system-based screening study of unselected individuals found to have a pathogenic variant associated with FH, EMR data was used to determine whether patients had a diagnosis of FH based on Dutch Lipid Clinic Criteria without information about their pathogenic variant. Of the carriers, there were 7.4% definite FH, 16.3% probable FH, and 31.6% possible FH. The remaining 44.7% of cases were unlikely to have a diagnosis of FH. (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
A meta-analysis of 4 retrospective observational studies estimated a higher risk for stroke in patients with HeFH compared to the general population (2 studies of 629 patients with HeFH; OR=7.66, 95% CI: 6.06-9.68) in the pre-statin era (defined as before 1987), but a lower risk for stroke in patients with HeFH (2 studies of 2745 patients with HeFH; OR=0.25, 95% CI: 0.18-0.36) following the generalization of statin therapy. (Tier 1)
A second meta-analysis of 6 cross-sectional and prospective cohort studies (minimum follow-up of 4 years) found that HeFH was associated with a higher risk of peripheral artery disease (PAD) relative to the general population (3 studies of 111,030 adults; OR: 3.59, 95% CI: 1.30-9.89), though this association was not significant when restricted to 2 studies defining HeFH using genetic criteria (OR=2.96, 95% CI: 0.68-12.88). HeFH was associated with a higher risk of ischemic stroke relative to the general population (4 studies of 182,662 adults with HeFH, OR: 1.62; 95% CI: 1.17-2.23), however this association was not significant when restricted to the 2 studies with genetically confirmed HeFH (OR: 0.76; 95% CI: 0.37-1.58). (Tier 1)
In a Danish population-based study of patients with FH (selected on clinical criteria) versus non-FH patients, the odds ratios for CAD were 10.3 (95% CI: 7.8–13.8) and 13.2 (95% CI: 10.0–17.4) in subjects treated and not treated with LLT, respectively. (Tier 1)
In an analysis of 12 observational studies (N=26,025), individuals high LDL-C (≥190 mg/dl) and no FH variant had 6-fold higher risk for CAD (OR: 6.0, 95% CI: 5.2–6.9) compared to those without a high LDL-C. When limited those with high LDL-C and an FH pathogenic variant, there was a 22-fold increased risk (OR: 22.3, 95% CI: 10.7–53.2). (Tier 3)
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Within a US health-system based screening study individuals with an FH variant had a higher risk of CAD (OR: 2.6, 95%CI: 2.0-3.5) and premature CAD (OR: 3.7, 95% CI: 2.6 to 5.2). (Tier 3)
Individuals with FH-causing variants are at a 5- to 22-fold increased risk of ASCVD compared with normolipidemic individuals. (Tier 3)
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Cardiovascular mortality in FH patients aged 20-39 years can be up to 100-times higher than in the same disease-free population. (Tier 3)
The risk of CHD among individuals with definite or probable HeFH is estimated to be increased at least 10-fold. (Tier 3)
Compared to the general population, there is a 4-times greater and 5-times greater risk for males and female adults, respectively, of CHD in the 40-59 age group based on combined pre-and post-statin era data from the Simon Broome Registry. (Tier 2)
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 4)
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 but absence of cardiovascular disease until late in life in a similar small percentage. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions for HeFH include invasive and non-invasive imaging, clinical monitoring, and medication. 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. 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. Trials of PCSK9 inhibitors, which are administered subcutaneously, indicate that there is no significant difference in the frequency of adverse events compared to those on placebo. The most frequently reported side effects of PCSK9 inhibitors are itching at the injection site and flu-like symptoms. 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
The majority of children and adolescents with FH are undiagnosed, as symptoms and signs only develop after decades of hypercholesterolemia. Many patients with FH remain unrecognized, particularly in countries that have not enacted a national registry. (Tier 3)
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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 Condition Associations
Condition Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
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