Summary
Clinical characteristics.
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or nonfatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years.
An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years.
In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
Diagnosis/testing.
Several formal diagnostic criteria exist for FH. The diagnostic criteria most widely used in Western countries include: extreme hypercholesterolemia (untreated adults with LDL-C>190 mg/dL or total cholesterol levels >310 mg/dL; untreated children/adolescents with LDL-C levels >160 mg/dL or total cholesterol levels >230 mg/dL); history of premature CAD or other CVD; xanthomas; corneal arcus; and a family history of features suggestive of FH. The diagnosis of FH can also be established by identification of a heterozygous pathogenic variant in one of the three genes (APOB, LDLR, and PCSK9) known to be associated with FH.
The diagnosis of HoFH can be established in a proband by identification of biallelic pathogenic variants in one of the three genes (APOB, LDLR, and PCSK9) known to be associated with FH.
Management.
Treatment of manifestations: Adults with FH: reduce CAD risk factors including cessation of smoking, regular physical activity, healthy diet, and weight control; treatment of hypertension; low-dose aspirin in high-risk individuals; pharmacotherapy (statins with additional medications as needed) to reduce lipid levels; referral to a lipid specialist if necessary to reduce LDL-C levels. Children with FH: referral to a lipid specialist; diet and lifestyle modifications; statins can be used in children starting around age eight years. Children and adults with HoFH: referral to a lipid specialist or specialized center for management of multiple drug therapy; LDL apheresis is often required; liver transplantation in rare circumstances.
Prevention of primary manifestations: Statin-based therapy with addition of other medications as needed, in combination with a heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; not smoking.
Surveillance: Children with an established diagnosis of FH or risk factors for FH (e.g., elevated serum cholesterol, a family history of FH, a family history of premature CAD or other CVD) should have lipid levels checked before age ten years. All individuals with FH should have lipid levels monitored as recommended. Individuals with HoFH should be monitored with various imaging modalities (including echocardiograms, CT angiograms, and cardiac catheterization) as recommended.
Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, excessive intake of cholesterol, sedentary lifestyle, obesity, hypertension, and diabetes mellitus.
Evaluation of relatives at risk: Early diagnosis and treatment of first-degree and second-degree relatives at risk for FH can reduce morbidity and mortality. The genetic status of at-risk family members can be clarified by either: (1) molecular genetic testing if the pathogenic variant has been identified in an affected family member; or (2) measurement of LDL-C concentration.
Pregnancy management: Pregnant women should incorporate all the recommended lifestyle changes including low saturated fat intake, no smoking, and high dietary soluble fiber. Statins are contraindicated in pregnancy due to concerns for teratogenicity and should be discontinued prior to conception. Bile acid binding resins (e.g., colesevelam) are generally considered safe (Class B for pregnancy), and LDL apheresis is also occasionally used if there is evidence of established CAD.
Genetic counseling.
Heterozygous familial hypercholesterolemia (FH) and homozygous familial hypercholesterolemia (HoFH) are inherited in an autosomal dominant manner.
Almost all individuals diagnosed with FH have an affected parent; the proportion of FH caused by a de novo pathogenic variant is unknown but appears to be extremely low. Each child of an individual with FH has a 50% chance of inheriting the pathogenic variant.
If both parents have FH, each child has a 50% chance of having FH, a 25% chance of having HoFH, and a 25% chance of not having FH.
If the pathogenic variant has been identified in a family member with FH (or if both pathogenic variants have been identified in a family member with HoFH), prenatal testing for pregnancies at increased risk is possible.
Diagnosis
In this GeneReview:
Familial hypercholesterolemia (FH) refers to hypercholesterolemia resulting from a
heterozygous pathogenic variant in one of several genes (
APOB,
LDLR, and
PCSK9); it is also referred to as heterozygous FH (HeFH). FH is a relatively common disorder (prevalence 1:200-1:250).
Suggestive Findings
Familial hypercholesterolemia (FH) should be suspected in individuals with the following findings:
Extreme hypercholesterolemia
History of premature coronary artery disease (CAD) or other cardiovascular disease (CVD) (e.g., angina pectoris, myocardial infarction, peripheral vascular disease)
Physical examination findings (e.g., xanthomas, corneal arcus)
Family history of premature CAD and/or CVD
Establishing the Diagnosis
Currently three formal diagnostic criteria for FH are widely used in Western countries: the MEDPED Criteria, the Simon Broom Criteria, and the FH Dutch Lipid Clinic Criteria. (See Harada-Shiba et al [2012] for criteria used in non-Western countries.)
All three criteria rely on a combination of the following:
Extreme hypercholesterolemia
History of premature CAD or other CVD
Findings on physical examination
Family history of premature CAD or other CVD
Extreme hypercholesterolemia
Note: (1) A non-fasting lipid panel can be obtained first in the initial evaluation of children, and, if abnormal or borderline, a fasting LDL-C level should be obtained [Martin et al 2013]. Elevation of two consecutive LDL-C levels is often recommended to confirm the diagnosis. (2) Age-specific LDL-C or total cholesterol levels are more specific in determining the likelihood of FH; for instance, LDL-C or total cholesterol levels >95th percentile for age, sex, and country [Starr et al 2008, Nordestgaard et al 2013]. (3) Computer (including mobile or smart phone-based) applications (see FH Diagnosis) can assist with the determination of the likelihood of FH based on the formal diagnostic criteria.
History of premature CAD or other CVD
Note: Although stroke is possible, it is less common in FH than premature CAD [Huxley et al 2003].
Physical examination findings
Xanthomas (patches of yellowish cholesterol buildup). Common locations include around the eyelids, tendons of the elbows, hands, knees, and feet, particularly the Achilles tendon. Interdigital xanthomas occur in individuals with
homozygous FH.
Corneal arcus (white, gray, or blue opaque ring in the corneal margin). Because this becomes increasingly common in the general population with age, it is only diagnostic in younger individuals, particularly before age 45 years.
Note: As statin treatment has become more common, it is possible that individuals have fewer visible signs of FH, complicating the application of the diagnostic criteria.
Family history of any of the following
Familial hypercholesterolemia
High levels of LDL-C
Early-onset (i.e., age <50 years) CAD (especially myocardial infarction)
Xanthomas
Identification of a pathogenic variant in a gene known to be associated with FH (see Table 1) is the gold standard for diagnosis accepted in many countries [Nordestgaard et al 2013].
Molecular genetic testing approaches can include serial single-gene testing and use of a multigene panel:
Serial single-gene testing can be considered. Sequence analysis of
LDLR is performed first and followed by
LDLR deletion/duplication analysis if no
pathogenic variant is found. Sequence analysis of
APOB and
PCSK9 can be performed next if no pathogenic variant is found.
A multigene panel that includes
APOB,
LDLR,
PCSK9, and other genes of interest (see
Differential Diagnosis) may also be considered. Note: (1) The genes included and the
sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Table 1.
Molecular Genetic Testing Used in Familial Hypercholesterolemia (FH)
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| Gene 1 | Proportion of FH Attributed to Pathogenic Variants in Gene 2 | Proportion of Pathogenic Variants 3 Detectable by Method |
|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 |
|---|
|
APOB
| 1%-5% | >99% | 1 person 6 |
|
LDLR
| 60%-80% | >90% 7 | ~2.5%-10% 8 |
|
PCSK9
| 0%-3% | ~100% | None reported 9 |
| Unknown 10, 11 | 20%-40% | NA |
- 1.
- 2.
The yield for genetic testing varies by the pre-test probability of the disease as determined by the clinical diagnostic criteria. In "definite" FH the yield of genetic testing for identification of a pathogenic variant approaches 95%; in "probable" or "possible" FH the yield is lower (~70%) [Motazacker et al 2012, Awan et al 2013].
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
- 7.
The majority of pathogenic variants in LDLR are detectable by sequence analysis, including those in the regulatory region (the majority occurring within 200 bp upstream of the initiation codon) if that region is targeted for sequencing [Dedoussis et al 2004].
- 8.
- 9.
- 10.
- 11.
It has been suggested that a polygenic etiology is most likely in the majority of persons with a clinical diagnosis of FH in whom no pathogenic variant in one of the three known genes can be identified. This suggestion is based on the presence in these individuals of a greater-than-average number of common LDL-C-raising variants (i.e., a high "LDL-SNP score") [Talmud et al 2013].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with familial hypercholesterolemia (FH) the following evaluations are recommended in adults and children:
Measurement of pre-treatment lipid values and lipoprotein(a) levels when possible
Exclusion of concurrent illnesses (kidney disease, acute myocardial infarction, infection) that can affect lipid values
Lipid panel including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides
Consultation with a lipid specialist or clinician with expertise in FH
Recommended in some guidelines: noninvasive imaging modalities in children (e.g., measurement of carotid intima-media thickness) to help inform treatment decisions [
Martin et al 2013]
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Adults with FH
All individuals with FH should be considered "high risk" for coronary artery disease (CAD) and should be treated actively to lower cholesterol levels. Note that standard Framingham or other risk classification schemes are not applicable [Goldberg et al 2011, Hopkins et al 2011, Stone et al 2014]. The most current recommendations (summarized here) for the management of FH used in the United States are from the American Heart Association [Gidding et al 2015] (full text) and largely reflect earlier recommendations from the National Lipid Association (NLA).
For adults, treatment should begin as soon as possible after diagnosis. All adults with FH require diet/lifestyle management, and almost without exception will also require cholesterol-lowering drug therapy.
Risk factors (e.g., smoking, diabetes mellitus, hypertension) are the same in FH as in the general population; aggressive management is required to reduce CAD risk, with special attention to smoking cessation.
Regular physical activity, a healthy diet (reduce saturated fat intake, increase intake of soluble fiber to 10-20 g/day), and weight control should be emphasized.
Blood pressure should be treated to 140/90mm Hg (or 130/80 mm Hg in those with diabetes mellitus).
Low-dose aspirin (75-81 mg/day) should be considered in those at high risk for CAD or stroke.
Consider referral to a lipid specialist with expertise in FH if LDL-C concentrations are not reduced with maximal medical therapy. (Note: Although it has not been specified, this recommendation generally pertains to LDL-C levels that cannot be reduced by ≥50% with maximal medical therapy over a 6-month period.)
For adults with FH age 20 years or older, treatment with statins should be initiated to reduce the LDL-C level ≥50% or to <100 mg/dL (<2.6 mmol/L) [
Hopkins et al 2011,
Nordestgaard et al 2013]. Many guidelines suggest a target LDL-C of <100 mg/dL even in those without known CAD as individuals with FH have had a lifelong burden of high LDL-C [
Gidding et al 2015].
For persons with FH with any of the following CAD risk factors, drug treatment may need to be intensified (see *Note) to achieve more aggressive treatment goals (LDL-C <100 mg/dL [<2.6 mmol/L] and non-HDL-C <130 mg/dL [<3.4 mmol/L]). Risk factors:
Clinically evident CAD or other atherosclerotic cardiovascular disease; the goal is LDL-C level of <70 mg/dL (<1.8 mmol/L)
Diabetes mellitus or metabolic syndrome
Family history of very early CAD (men age <45 years; women age <55 years)
Current smoking
High lipoprotein(a) (≥50 mg/dL [≥1.3 mmol/L] using an isoform insensitive assay)
The second-line agent for individuals with FH who do not achieve acceptable LDL-C levels is generally ezetimibe. Treatment options for intensification of therapy after ezetimibe or for those intolerant of statins include bile acid sequestrants and/or PCSK9 inhibitors. Although niacin has been used as an adjunctive therapy in individuals with FH, given recent data, niacin is generally not favored before the other options have been exhausted [Guyton et al 2013, FDA 2016] (see Table 3).
In persons with FH without any of the CAD risk factors listed above, intensification of drug therapy (see *Note) should be strongly considered if 50% reduction in LDL-C is not achieved after six months on maximum statin therapy. For adults, some guidelines call for intensification of treatment if the goal LDL-C of <100 mg/dL (<2.6 mmol/L) is not achieved [Nordestgaard et al 2013].
*Note: (1) The lipid-lowering therapy should initially be statin-based with titration of doses every few months in order to use the highest tolerated dose of a potent statin, followed by addition of other drugs if the targeted LDL-C level is not achieved. (2) The potential benefit of multidrug regimens should be weighed against the increased cost and potential for adverse effects and decreased adherence.
Table 3.
Current Recommended Drug Therapies for Adults with FH
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| Class | Primary (1O) and Secondary (2O) Mechanism of Action | LDL-Lowering Response |
|---|
| Statins | ↑ LDLR activity (1O) | >35% 1, 2 |
| Cholesterol absorption inhibitors (ezetimibe) | ↓ Cholesterol absorption (1O)
↑ LDLR activity (2O) | 15% 1, 3 |
| Mipomersen (APOB antisense) 4 | Blocks APOB production in the liver | 50% 5 |
MTP inhibitor
(lomitapide) 4 | ↓ microsomal triglyceride transfer protein activity (1O)
Inhibition of LDL production (2O) | 50% 5 |
PCSK9 inhibitors
(alirocumab, evolocumab) | ↓ LDL-receptor degradation | 50% 6 |
Bile acid sequestrants
(cholestyramine, colesevelam) | ↓ Bile acid reabsorption (1O)
↑ LDLR activity (2O) | 15% 1, 3 |
| Stanol esters | ↓ Cholesterol absorption (1O)
↑ LDLR activity (2O) | 10% 1, 3 |
Some guidelines call for the addition of n-3 polyunsaturated fatty acids or fibrates if triglycerides remain elevated after the LDL-C is controlled.
- 1.
Often ineffective in HoFH
- 2.
- 3.
- 4.
Approved only for adults with HoFH
- 5.
- 6.
Children with FH
Guidelines for the management of children and individuals up to age 21 years have been published by the National Heart, Lung, and Blood Institute (full text). Children should be considered for drug treatment with statin-based regimens when:
US-based guidelines from the NLA (full text):
Consultation or referral to a lipid specialist is recommended.
Management of diet and physical activity is recommended at an early age.
Statins are the preferred initial pharmacologic treatment in children. Consideration should be given to starting statin treatment at age eight years or older. In special cases, such as children with
homozygous FH, drug treatment needs to be initiated prior to age eight years.
The goal of lipid-lowering therapy in children with FH is a ≥50% reduction in LDL-C or LDL-C <130 mg/dL (<3.4 mmol/L). Note: More aggressive lowering of LDL-C levels should be considered for children with additional CAD risk factors (e.g., family history of CAD, high blood pressure, unhealthy diet or exercise behaviors, obesity).
Children and Adults with Homozygous FH (HoFH)
NLA guidelines for homozygous FH (full text):
Referral to a lipid specialist is indicated.
Early initiation of therapy and monitoring are recommended.
Multiple drug therapy is usually needed. Several different classes of medications are currently being used to treat HoFH (see
Table 3).
Since many cholesterol-lowering medications target the LDL receptor, effectiveness in persons with FH with
biallelic loss-of function
LDLR pathogenic variants can be limited [
Cuchel et al 2014]. Statins are often relatively ineffective in the treatment of HoFH because their efficacy largely depends on the upregulation of functional LDL receptors in the liver. In HoFH, both copies of the LDL receptor have absent or greatly reduced activity [
Raal & Santos 2012].
High-dose statins, ezetimibe, and bile-acid binding resins may be effective in some persons with HoFH, especially those with some residual LDLR activity.
For HoFH, evolocumab is a PCSK9 inhibitor that showed a 40% mean reduction in LDL-C compared with placebo; however, individuals with two
loss-of-function variants saw no response [
Raal et al 2015]. PCSK9 inhibitors have not been formally approved in children with FH.
HoFH-specific medications (lomitapide and mipomersen) are effective even with complete loss of LDL receptor function and – though not formally FDA approved for children – should strongly be considered.
Despite these options, many individuals with HoFH (especially those with complete loss of LDL receptor function) will require ongoing LDL apheresis. LDL apheresis (≤2x/week) is often required starting from a young age. Apheresis can lower LDL-C levels by 80% acutely and 30% chronically (weekly or biweekly). Apheresis is offered at a limited number (~40-50) of centers in the United States; many states do not have an apheresis center.
Liver transplantation is also being used in rare circumstances in some centers [
Martinez et al 2016]
Prevention of Primary Manifestations
Preventive measures include the following:
Statin-based therapy with addition of other medications as needed
Reduced intake of saturated fat
Increased intake of soluble fiber to 10-20 g/day
Increased physical activity
Not smoking
Surveillance
Children. Guidelines for the management of children have been published by multiple national and international organizations [Daniels et al 2008, DeMott et al 2008, Descamps et al 2011, Martin et al 2013] (see Published Guidelines / Consensus Statements).
A child who has a family history of FH or of premature CAD, who is heterozygous for the FH pathogenic variant in his or her family, or who has an elevated serum cholesterol concentration should have lipid levels checked starting as early as age two years [Goldberg et al 2011]. It is reasonable to check a non-fasting lipid level first and, if borderline, to follow with measurement of LDL-C. Some guidelines state that elevation of two consecutive measures of LDL-C are needed to confirm a diagnosis of FH [Martin et al 2013].
An LDL-C level of >130 mg/dL (>3.4 mmol/L) in a child is suspicious for FH and an LDL of >160 mg/dL (>4.1 mmol/L) is relatively specific for FH.
During treatment, individuals of any age with:
Agents/Circumstances to Avoid
The following should be avoided:
Evaluation of Relatives at Risk
The CDC has classified FH as a Tier 1 condition indicating a significant benefit from performing family-based cascade screening using cholesterol testing with or without DNA analysis on relatives of affected persons with FH in order to identify previously unknown cases of FH and provide those people with lifesaving treatment. Early diagnosis and treatment of relatives at risk for FH can reduce morbidity and mortality [Goldberg et al 2011, Ned & Sijbrands 2011, Reiner et al 2011].
The genetic status of at-risk family members can be clarified by EITHER of the following:
Molecular genetic testing if the
pathogenic variant has been identified in an affected family member
Measurement of LDL-C level.
Table 4 provides age-specific total cholesterol and LDL-C levels [
Williams et al 1993]. Note: Age-specific LDL cut-offs are also available based on more contemporary data from the United Kingdom [
Starr et al 2008].
Table 4.
Total and LDL Cholesterol Levels in Heterozygotes for FH Based on Degree of Relatedness to an Individual with FH
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| Degree of Relatedness to an Affected Individual | First Degree 1 | Second Degree 2 | Third Degree 3 |
|---|
| Cholesterol Levels | Total Cholesterol (LDL Cholesterol) in mg/dL |
|---|
|
Age
| <20 | 220 (155) | 230 (165) | 240 (170) |
| 20-29 | 240 (170) | 250 (180) | 260 (185) |
| 30-39 | 270 (190) | 280 (200) | 290 (210) |
| 40+ | 290 (205) | 300 (215) | 310 (225) |
- 1.
A parent, sib, or child. First-degree relatives share about half of their genes.
- 2.
An uncle, aunt, nephew, niece, grandparent, grandchild, or half-sib. Second-degree relatives share about one quarter of their genes.
- 3.
A first cousin, great-grandparent, or great-grandchild. Third-degree relatives share about one eighth of their genes.
Of note, all national and international guidelines for FH call for "cascade testing" of relatives at risk (i.e., systematic testing of first- and second-degree relatives of the index case [proband]). Evidence supports the use of genetic testing in cascade testing algorithms to improve the detection of FH [DeMott et al 2008, Wierzbicki et al 2008, Wald et al 2016].
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Statins are contraindicated during pregnancy; women with FH who are considering a pregnancy should be counseled of this risk and statins should be discontinued prior to conception.
Pregnant women should incorporate all the other recommended lifestyle changes including low saturated and trans unsaturated fat intake, no smoking, and high dietary soluble fiber intake (see Agents/Circumstances to Avoid).
Pharmacologic treatment
during pregnancy
Statins are contraindicated in pregnancy due to concerns for teratogenicity. The use of statins during human pregnancy has not definitively been associated with adverse fetal outcome; however, the role of cholesterol in embryologic development has led to theoretic concerns about the effect of these medications on a developing fetus and a recommendation that alternative medications be considered during pregnancy and lactation. Nursing mothers should not take statins.
Bile acid binding resins (colesevelam, cholestyramine) are generally considered safe (Class B for pregnancy). Based primarily on animal studies, cholestyramine use during pregnancy has not been associated with an increased risk of fetal anomalies. However, use of cholestyramine could theoretically cause depletion of maternal fat-soluble vitamins, including vitamin K.
LDL apheresis is also occasionally used.
Regarding other agents:
PCSK9 inhibitors. Use during pregnancy has not been well studied.
Ezetimibe. Use during human pregnancy has not been well studied.
Niacin. The use of pharmacologic doses of niacin, an essential vitamin, has not been studied in human pregnancy. The recommended upper limit of niacin intake during pregnancy is 30-35 mgs/day; higher doses have been associated with toxicity.
Therapies Under Investigation
CAD outcome trials of PCSK9 inhibitors are currently underway.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members
Heterozygous Familial Hypercholesterolemia (FH)
Parents of a proband
Almost all individuals diagnosed with FH have an affected parent.
A
proband with FH may have the disorder as the result of a
de novo pathogenic variant. Because
simplex cases (i.e., a single occurrence in a family) have not yet been evaluated sufficiently to determine if the pathogenic variant occurred
de novo, the proportion of FH caused by
de novo pathogenic variants is unknown but appears to be very low.
If the
pathogenic variant found in the
proband cannot be detected in leukocyte DNA of either parent, two possible explanations are
germline mosaicism in a parent or a
de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
Recommendations for the evaluation of parents of a
proband with an apparent
de novo pathogenic variant include
molecular genetic testing if the pathogenic variant has been identified in the proband, or cholesterol testing if the pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
Note: Although most individuals diagnosed with FH have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
Sibs of a proband
The risk to the sibs of the
proband depends on the genetic status of the proband's parents.
If both parents of the
proband are affected with FH or have a
pathogenic variant, the risk to sibs of having FH is 50%, the risk to sibs having HoFH is 25%.
When the parents are clinically unaffected, the risk to the sibs of a
proband appears to be very low.
The sibs of a
proband with clinically unaffected parents are still at increased risk for
familial hypercholesterolemia because of the possibility of reduced
penetrance in a parent. However, this is a very unlikely scenario.
If the
pathogenic variant found in the
proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the theoretic possibility of parental
germline mosaicism.
Offspring of a proband
Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a pathogenic variant, his or her family members may be at risk.
Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.
Homozygous Familial Hypercholesterolemia (HoFH)
Parents of a proband
The parents of an affected individual are obligate heterozygotes and thus have one
familial hypercholesterolemia-related
pathogenic variant.
Sibs of a proband. The risk to sibs of having FH is 50%; the risk to sibs of having HoFH is 25%.
Offspring of a proband. The offspring of an individual with HoFH are obligate heterozygotes for a pathogenic variant; thus, all will have FH.
Other family members. Sibs of the proband's parents are at 50% risk of having a pathogenic variant and, thus, FH.
Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant has been identified in a family member with FH (or both pathogenic variants have been identified in a family member with HoFH), prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Familial Hypercholesterolemia: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Table B.
View in own window
|
107730 | APOLIPOPROTEIN B; APOB |
|
143890 | HYPERCHOLESTEROLEMIA, FAMILIAL, 1; FHCL1 |
|
144010 | HYPERCHOLESTEROLEMIA, FAMILIAL, 2; FHCL2 |
|
603776 | HYPERCHOLESTEROLEMIA, FAMILIAL, 3; FHCL3 |
|
606945 | LOW DENSITY LIPOPROTEIN RECEPTOR; LDLR |
|
607786 | PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 9; PCSK9 |
APOB
Gene structure.
APOB is 42,216 base pairs in length, comprising 28 introns and 29 exons. It has an open reading frame of 13,692 bases.
The distribution of the introns within the gene is unusual in that 24 of the 29 introns occur in the 5' terminus. More than half of the protein is coded by the 7,572-bp exon 26, one of the largest exons reported in the human genome. One of the two main isoforms, apoB-100, synthesized exclusively in the liver, is responsible for complications related to FH [Whitfield et al 2004]. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. More than five pathogenic variants have been reported to be associated with FH, two of which are repeatedly found to be significant:
Pathogenic variants in this locus account for approximately 1%-5% of all persons with FH.
See also Table A, ClinVar.
Table 5.
APOB Selected Pathogenic Variants
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DNA Nucleotide Change
(Alias 1) | Predicted Protein Change
(Alias 1) | Reference Sequences |
|---|
c.10580G>A 2
(9775G>A) | p.Arg3527Gln
(Arg3500Gln) |
NM_000384.2
NP_000375.2
|
c.10579C>T
(9774C>T) | p.Arg3527Trp
(Arg3500Trp) |
| c.10672C>T | p.Arg3558Cys |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Amino acids are numbered from the beginning of the protein precursor, including signal sequence, and nucleotides from first base of the ATG initiation codon.
- 1.
Variant designation that does not conform to current naming conventions. In this case, numbering is based on mature peptide before cleavage of signal peptide and corresponding nucleotides.
- 2.
Normal gene product. The gene product is the main apolipoprotein of chylomicrons and low-density lipoproteins. Human APOB mRNA is 14.5 kb in length and codes for a mature protein of 4,560 amino acids [UCSC Genome Browser, APOB; accessed July 10, 2013].
APOB has four functional domains [Innerarity et al 1990]:
Synthesis, assembly, and secretion of hepatic triglyceride-rich lipoproteins
Binding of lipids and serving as a structural component of very low-density lipoproteins (VLDL) and LDL
Binding of heparin and various proteoglycans found in the arterial wall
Interaction with the LDL receptor, important for clearance of LDL from plasma
Abnormal gene product.
APOB is generally involved in aiding the binding of LDL-C to its receptor on the cell surface. APOB pathogenic variants alter the ability of protein to effectively bind LDL-C to LDLR, causing fewer LDL-C particles to be removed from the blood.
LDLR
Gene structure.
LDLR spans 45 kb, comprising 18 exons and 17 introns. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Pathogenic variants have been reported in the promoter, introns, and exons of LDLR. The majority of pathogenic variants fall within the ligand-binding (40%) or epidermal growth factor precursor-like (47%) domains, with the highest frequency of pathogenic variants reported in exon 4 (20%) [Leigh et al 2008, Usifo et al 2012]. More than 1,500 LDLR pathogenic variants have been reported in the University College London (UCL) database, highlighting the molecular heterogeneity of the disorder. See Table A, Locus-Specific Databases and ClinVar, for a list of reported variants.
Table 6.
LDLR Selected Pathogenic Variants
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
Normal gene product.
LDLR encodes a mature protein product of 839 amino acids [NP_000518.1]. LDLR has four distinct functional domains that can function independently of each other [NCBI Conserved LDLR Domains; accessed July 10, 2013]:
LDLR consists of cell surface proteins involved in endocytosis of LDL cholesterol (LDL-C). After LDL-C is bound at the cell membrane, it is taken into the cell and to lysosomes where the protein moiety is degraded and the cholesterol molecule suppresses cholesterol synthesis via negative feedback.
Abnormal gene product. Pathogenic variants in LDLR usually either reduce the number of LDL receptors produced within the cells or disrupt the ability of the receptor to bind LDL-C. Either way, heterozygous pathogenic variants in LDLR cause high levels of plasma LDL-C [UCSC Genome Browser, LDLR; accessed July 10, 2013].
PCSK9
Gene structure.
PCSK9 has a transcript size of 25,378 bp and 12 exons. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Approximately 100 variants in PCSK9 have been submitted to the University College London database [Abifadel et al 2003]. Although many are hypothesized to be pathogenic, few have been consistently and significantly associated with FH [Naoumova et al 2005]. For a complete list of reported variants, see Table A, Locus-Specific Databases and ClinVar.
Table 7.
PCSK9 Selected Pathogenic Variants
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| DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
|---|
| c.381T>A | p.Ser127Arg |
NM_174936.3
NP_777596.2
|
| c.644G>A | p.Arg215His |
| c.646T>C | p.Phe216Leu |
| c.1120G>T | p.Asp374Tyr |
| c.1486C>T | p.Arg496Trp |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
PCSK9 encodes a protein consisting of 692 amino acids and three main domains:
Abnormal gene product. The PCSK9 protein product binds to LDL lipid receptors and promotes their degradation in intracellular acidic compartments.
Pathogenic variants in this gene have been associated both with hypercholesterolemia and hypocholesterolemia.
