Clinical characteristics.

Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely. Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels. Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids. Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH.

Individuals with a more severe phenotype, often as a result of biallelic variants, can present with very significant elevations in LDL-C (>500 mg/dL), early-onset coronary artery disease (CAD; presenting as early as childhood in some), and calcific aortic valve disease.

Diagnosis/testing.

A clinical diagnosis of FH can be established in a proband with characteristic clinical features and significantly elevated LDL-C levels (typically >190 mg/dL in adults and >160 mg/dL in children). Three formal diagnostic criteria are used in Western countries.

The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1.

Management.

Treatment of manifestations: Adults: pharmacotherapy (statins with additional medications as needed) to reduce lipid levels; referral to a lipid specialist if necessary to reduce LDL-C levels; 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. Children: referral to a lipid specialist; diet and lifestyle modifications; statins can be used in children starting around age eight years.

Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking.

Surveillance: Monitor lipid levels from age two years; consider noninvasive imaging modalities in adults; identify modifiable risk factors (e.g., smoking, sedentary behavior, hypertension, diabetes, obesity). Individuals with severe FH (i.e., due to homozygous or compound heterozygous pathogenic variants in APOB, LDLR, or PCSK9) or autosomal recessive FH (due to homozygous or compound heterozygous pathogenic variants in LDLRAP1) should be monitored with various imaging modalities (including echocardiogram, CT angiogram, and cardiac catheterization) as recommended.

Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, 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(s) has been identified in an affected family member; or (2) measurement of LDL-C concentration. Genetic testing is the preferred method for clarifying the diagnosis in at-risk family members, when possible.

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 because of 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 used occasionally if there is evidence of established CAD. Use of PCSK9 inhibitors, ezetimibe, lomitapide, and bempedoic acid during pregnancy has not been well studied.

Genetic counseling.

APOB-, LDLR-, and PCSK9-related FH are inherited in an autosomal dominant manner. If an individual has biallelic (homozygous or compound heterozygous) pathogenic variants in one of these three genes – a condition referred to as homozygous FH (HoFH) – the presentation becomes more severe with earlier onset of features. Some individuals with FH are heterozygous for pathogenic variants in two different FH-related genes, which may have an additive effect on the severity of FH. Each child of an individual with a heterozygous pathogenic variant in APOB, LDLR, or PCSK9 has a 50% chance of inheriting the pathogenic variant and having FH. All children of an individual with homozygous FH will inherit a pathogenic variant and have FH. If the reproductive partner of a proband is heterozygous for an FH-related pathogenic variant in the same gene as the proband or a different FH-related gene, offspring are at risk of inheriting two pathogenic variants and having severe FH.

LDLRAP1-related FH is caused by biallelic pathogenic variants and is inherited in an autosomal recessive manner. The parents of an individual with LDLRAP1-related FH are presumed to be heterozygous for one pathogenic variant. If both parents are known to be heterozygous for an LDLRAP1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Carrier testing for at-risk relatives requires prior identification of the LDLRAP1 pathogenic variants in the family.

Once the FH-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Familial hypercholesterolemia (FH) should be suspected in individuals with the following findings.

Extreme hypercholesterolemia

• Adults (untreated):
  • Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L)
  • Total cholesterol levels >310 mg/dL (>8 mmol/L)
• Children/adolescents (untreated):
  • LDL-C levels >190 mg/dL (≥4.9 mmol/L) [Wiegman et al 2015, de Ferranti et al 2019]
  • LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [Wiegman et al 2015, Sturm at al 2018, de Ferranti et al 2019]
  • LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [Wiegman et al 2015]
  • Total cholesterol levels >230 mg/dL (>6 mmol/L)

History of premature coronary artery disease (CAD) such as myocardial infarction or obstructive CAD requiring intervention or other cardiovascular disease (e.g., ischemic stroke, peripheral vascular disease). Premature CAD is typically defined as disease identified before age 55 years in males and before age 65 years in females.

Physical examination findings

• Xanthomas (cholesterol deposits in tendons) may be identified in adults but are unlikely to present in children with heterozygous familial hypercholesterolemia (HeFH).
  Note: Xanthomas can present within the first few years of life in those with a more severe phenotype due to biallelic variants [Wiegman et al 2015].
• Xanthelasmas (yellowish, waxy deposits that can occur around the eyelids)
• Corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) is more likely to be FH-related when present in an individual younger than age 45 years.

Family history of any of the following:

• FH
• Elevated LDL-C levels
• Premature CAD
• Xanthomas/xanthelasmas

Note: (1) Age-specific LDL-C or total cholesterol levels are more specific in determining the likelihood of FH (e.g., >95th percentile for age, sex, and country) [Nordestgaard et al 2013]. (2) Electronic applications (see FH Diagnosis) can assist with the determination of the likelihood of FH based on the formal diagnostic criteria.

Establishing the Diagnosis

The clinical diagnosis of FH can be established in a proband with features described in Suggestive Findings. Currently three formal diagnostic criteria for FH are widely used in Western countries: the MEDPED Criteria, the Simon Broome Criteria, and the FH Dutch Lipid Clinic Network Criteria. (See Harada-Shiba et al [2012] for criteria used in non-Western countries.) All use various FH-related features to establish the diagnosis (e.g., LDL-C levels, history of CAD, physical examination findings, family history); LDL-C levels are incorporated into all three criteria.

Note: The criteria used to establish the clinical diagnosis of FH in children varies substantially across medical centers within and outside of the United States. Some experts recommend the Simon Broome criteria in pediatric probands rather than the Dutch Lipid Clinic Network Criteria [Wiegman et al 2015].

A molecular diagnosis of FH can be established in a proband by identification of:

• A heterozygous pathogenic (or likely pathogenic) variant in LDLR
• A heterozygous pathogenic (or likely pathogenic) variant in APOB (impairing binding of LDL-C to the LDL receptor)
• A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in PCSK9
  Note: A whole-gene duplication of PCSK9 has also been described in individuals with severe FH [Iacocca et al 2018].
• Biallelic loss-of-function pathogenic (or likely pathogenic) variants in APOB, LDLR, LDLRAP1, or biallelic gain-of-function pathogenic (or likely pathogenic) variants in PCSK9 (associated with severe FH).

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a smaller FH multigene panel or a broader dyslipidemia multigene panel depending on the phenotype:

• A smaller FH multigene panel that includes sequence analysis and deletion/duplication analysis of APOB, LDLR, LDLRAP1, and PCSK9 may be considered.
• A broader dyslipidemia multigene panel that includes APOB, LDLR, LDLRAP1, and PCSK9 as well as ABCG8, ABCG5, APOE, and LIPA (genes associated with other lipid conditions that can cause elevated LDL-C levels and early-onset CAD; 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.

Clinical Description

Heterozygous Familial Hypercholesterolemia (FH; HeFH)

Elevated low-density lipoprotein cholesterol (LDL-C) leads to atherosclerotic plaque deposition in the coronary arteries and other arterial beds starting at an early age and worsening over time. Individuals with FH have elevated LDL-C levels starting soon after birth. When left untreated, this can lead to an increased risk of angina, myocardial infarction, peripheral artery disease, and potentially stroke [Scientific Steering Committee 1991, Versmissen et al 2008, Elis et al 2011, Raal & Santos 2012]. Individuals with an LDL-C greater than 190 mg/dL (>4.9 mmol/L) and a pathogenic variant in one of the genes listed in Table 1 have a 22-fold increased risk for coronary artery disease (CAD) over the general population, while those without a pathogenic variant have a sixfold increased risk for CAD over the general population [Khera et al 2016]. Natural history studies from the pre-statin era suggest that untreated men are at 50% risk for a fatal or nonfatal coronary event by age 50 years; untreated women are at 30% risk by age 60 years [Slack 1969, Stone et al 1974, Civeira 2004, Goldberg et al 2011, Reiner et al 2011] (Figure 1). Additional studies have found that approximately one in ten individuals with a history of early-onset myocardial infarction have FH, and this risk increased in the setting of a family history of CAD [Singh et al 2019]. Of note, standard Framingham or other risk classification schemes are not applicable to persons with FH [Goldberg et al 2011, Reiner et al 2011, Nordestgaard et al 2013]. The risk of stroke in individuals with FH is less clear, with some studies finding that this risk may not be as strongly correlated with FH as initially thought [Akioyamen et al 2019, Hovland et al 2019].

Figure 1.

LDL cholesterol burden in individuals with or without familial hypercholesterolemia as a function of the age of initiation of statin therapy Data derived from Starr et al [2008] and Huijgen et al [2012]. Figure from Nordestgaard et al [2013]; used by (more...)

Lipid-lowering therapy with statin-based regimens (see Management, Treatment of Manifestations) significantly increases survival [Nordestgaard et al 2013, Vuorio et al 2013] and reduces morbidity [Versmissen et al 2008, Elis et al 2011, Braamskamp et al 2016]. Additional medications such as ezetimibe, bile acid-binding resins, PCSK9 inhibiters, or bempedoic acid are often necessary to achieve optimal LDL-C reduction [Gidding et al 2015]. LDL-C levels are typically unable to be lowered with lifestyle intervention alone.

Xanthomas represent cholesterol buildup in tendons of the body as a result of extremely high levels of LDL-C. Xanthomas may worsen with age in untreated persons. In persons treated with LDL-C-lowering therapy, the xanthomas can become smaller. Common locations:

• Tendonous xanthomas can occur in the elbows, hands, knees, and feet, particularly the Achilles tendon [Tsouli et al 2005, Elis et al 2011]. These are historically described in 30%-50% of persons with FH, although more recent studies show a lower prevalence, likely because of widespread statin use [Perez de Isla et al 2016].
• Interdigital xanthomas (between the fingers) occur in individuals with biallelic pathogenic variants in APOB, LDLR, or PCSK9.

Xanthelasmas are patches of yellowish cholesterol deposits that often occur around the eyes [Dey et al 2013].

Corneal arcus (white, gray, or blue opaque ring in the corneal margin) is caused by abnormal deposition of lipids in the cornea secondary to long-term exposure to elevated LDL-C levels. This feature develops with age and is concerning for FH when identified before age 45 years. Studies have found that this feature may present in an estimated 7%-30% of individuals with FH [Perez de Isla et al 2016, Rizos et al 2018]. It is less likely to be identified in children with heterozygous FH-related pathogenic variants and in individuals who have been on lipid-lowering medications from a young age. This feature does not resolve with treatment.

Phenotype Correlations by Gene

Penetrance

APOB. Penetrance for FH may be reduced in persons with a heterozygous APOB variant [Doi et al 2021, Kamar et al 2021].

LDLR. Studies report that only 73% of individuals with a heterozygous LDLR variant (especially partial loss-of-function variants) have an LDL-C level >130 mg/dL, suggesting lower penetrance than previously proposed [Khera et al 2016].

PCSK9

• Penetrance is approximately 90% in persons heterozygous for the c.381T>A (p.Ser127Arg) pathogenic variant [Dullaart 2017].
• Penetrance in persons heterozygous for the p.Asp374Tyr pathogenic variant is high, with FH manifesting at a young age [Naoumova et al 2005].
• Penetrance for other heterozygous PCSK9 variants remains largely unknown [Cariou et al 2011].

Nomenclature

While the term "homozygous" is generally used in genetics to denote the presence of the same pathogenic variant in both alleles of a given gene, the term "homozygous FH" or "HoFH" is used in the medical literature to denote the presence of any two pathogenic variants (compound heterozygous or homozygous) on both alleles of APOB, LDLR, or PCSK9.

The term "autosomal recessive FH" refers to FH caused by biallelic pathogenic variants in LDLRAP1.

Prevalence

The prevalence of HeFH in the general population was traditionally cited as 1:500; however, data suggest that it may be as high as ~1:250 [Benn et al 2012, Nordestgaard et al 2013]. This prevalence has been primarily based on studies from Europe, North America, East Asia, and Australia. The prevalence of HeFH remains unknown in 90% of countries in the world, including countries in Africa, Asia, and South America [Beheshti et al 2020, Hu et al 2020].

The prevalence of HoFH due to biallelic pathogenic variants in APOB, LDLR, or PCSK9 is estimated at 1:160,000 to 1:400,000 [Nordestgaard et al 2013, Cuchel et al 2014, Beheshti et al 2020].

The prevalence of autosomal recessive FH due to biallelic pathogenic variants in LDLRAP1 is lower than 1:1,000,000 [D'Erasmo et al 2020]. An increased carrier frequency of 1:143 in Sardinia, Italy, for autosomal recessive LDLRAP1-related FH is the result of founder variants (see Table 11).

FH is more common in several populations (Table 3) because of founder variants (see Table 11).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with familial hypercholesterolemia (FH), the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Prevention of Primary Manifestations

To prevent primary manifestations, the following are recommended:

• Reduce saturated fat intake.
• Increase intake of soluble fiber to 10-20 g/day.
• Increase physical activity.
• Do not smoke.

Surveillance

During treatment, individuals of any age with:

• FH should have lipid levels monitored as recommended;
• Severe FH (HoFH due to homozygous or compound heterozygous pathogenic variants in APOB, LDLR, or PCSK9, or autosomal recessive FH due to homozygous or compound heterozygous pathogenic variants in LDLRAP1) should be monitored with various imaging modalities (including echocardiogram, CT angiogram, and cardiac catheterization) as recommended [Raal & Santos 2012].

Additional recommended evaluations include those in Table 8.

Agents/Circumstances to Avoid

The following should be avoided:

• Smoking
• High intake of saturated and trans unsaturated fat
• Sedentary lifestyle
• Obesity
• Hypertension
• Type II diabetes mellitus

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. Cholesterol testing, with or without molecular testing in relatives of affected persons with FH, can be used to identify individuals with FH and provide them with lifesaving treatment. Early diagnosis and treatment of relatives at risk for FH can reduce morbidity and mortality [Knowles et al 2017, Sturm et al 2018].

The genetic status of at-risk family members can be clarified by EITHER of the following:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Measurement of low-density lipoprotein cholesterol (LDL-C) level if the pathogenic variant(s) in the family are not known.

In children with a family history of FH, non-fasting lipid level should be measured by age two years. If lipid level is borderline, measure LDL-C level. An LDL-C level of >130 mg/dL in a child is suspicious for FH in the setting of a known family history of FH, and an LDL-C level of >160 mg/dL is relatively specific for FH.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

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.

Pharmacologic treatment during pregnancy:

• Statins are contraindicated in pregnancy because of concerns for teratogenicity; women with FH who are considering a pregnancy should be counseled of this risk and statins should be discontinued prior to conception. The use of statins during human pregnancy has not been definitively 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.
• Use of PCSK9 inhibitors, ezetimibe, lomitapide, and bempedoic acid during pregnancy has not been well studied.

Therapies Under Investigation

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.

Mode of Inheritance

APOB-, LDLR-, and PCSK9-related familial hypercholesterolemia (FH) are inherited in an autosomal dominant manner. If an individual has biallelic (homozygous or compound heterozygous) pathogenic variants in one of these three genes – a condition referred to as homozygous FH or HoFH – the presentation becomes more severe with earlier onset of features. The spectrum of severity in HoFH depends on the genes affected and impact of the pathogenic variant on protein function [Trinder et al 2020a, Trinder et al 2020b]. Some individuals with FH are heterozygous for pathogenic variants in two different FH-related genes, which may have an additive effect on the severity of FH [Kamar et al 2021].

LDLRAP1-related FH (reported to have a presentation similar to LDLR-related HoFH) is caused by biallelic pathogenic variants and is inherited in an autosomal recessive manner.

APOB-, LDLR-, and PCSK9-Related FH – Risk to Family Members

Parents of a proband

• Almost all individuals with FH resulting from a heterozygous pathogenic variant in APOB, LDLR, or PCSK9 have an affected parent.
• The proportion of probands with FH who have a de novo pathogenic variant is unknown but appears to be very low.
• Recommendations for the parents of the proband include the following:
  • Measurement of cholesterol (recommended for both the parents of a proband with a known APOB, LDLR, or PCSK9 pathogenic variant or with a clinical diagnosis of FH in the absence of a known FH-causing pathogenic variant) [Knowles et al 2017] (See Management, Evaluation of Relatives at Risk.)
  • Targeted molecular genetic testing if an APOB, LDLR, or PCSK9 pathogenic variant has been identified in the proband
• If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• 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, lack of knowledge regarding family member's cholesterol levels and heart disease history, or late onset of the disorder in the affected parent. If heterozygous family members have been on statins for many years, there may not be a prominent family history of premature CAD. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• The parents of an individual with biallelic pathogenic variants in APOB, LDLR, or PCSK9 are obligate heterozygotes and are thus presumed to have FH [Mabuchi et al 2014].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If one parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of having FH is 50%.
• If both parents of the proband are affected with FH and are known to have an FH-related pathogenic variant, there is a 50% risk that sibs will inherit one pathogenic variant and have FH, a 25% risk that sibs will inherit two pathogenic variants and have severe FH, and a 25% chance that sibs will inherit neither of the familial pathogenic variants.
  The severity of HoFH varies. HoFH caused by homozygous loss-of-function LDLR pathogenic variants is typically associated with the most severe presentation, followed by HoFH caused by compound heterozygous LDLR pathogenic variants [Cuchel et al 2014, Bertolini et al 2020].
• If the proband has a known FH-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. All sibs should undergo predictive genetic testing and cholesterol screening.
• If the parents are clinically unaffected but their genetic status is unknown, sibs should still be considered at risk for FH because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. All sibs should undergo predictive genetic testing and cholesterol screening.

Offspring of a proband

• Each child of an individual with FH caused by a heterozygous pathogenic variant in APOB, LDLR, or PCSK9 has a 50% chance of inheriting the pathogenic variant and having FH.
• All children of an individual with HoFH (i.e., biallelic FH-related pathogenic variants) will inherit a pathogenic variant and have FH.
• If the reproductive partner of a proband is heterozygous for an FH-related pathogenic variant in the same gene as the proband or a different FH-related gene, offspring are at risk of inheriting two pathogenic variants and having severe FH. Cholesterol screening – followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH – should be offered to the reproductive partner to assess this risk. (FH is more common in several populations [see Prevalence] as a result of founder variants.)

Other family members. The risk to other family members depends on the status of the proband's parents: if one or both parents have an FH-related pathogenic variant, sibs and parents of the proband's parents are at 50% risk of having a pathogenic variant and, thus, FH.

LDLRAP1-Related Autosomal Recessive FH – Risk to Family Members

Parents of a proband

• The parents of an individual with LDLRAP1-related FH are presumed to be heterozygous for one pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an LDLRAP1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous (i.e., the same two) pathogenic variants, additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for an LDLRAP1 pathogenic variant (i.e., carriers) are typically asymptomatic.

Sibs of a proband

• If both parents are known to be heterozygous for an LDLRAP1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Individuals who are heterozygous for an LDLRAP1 pathogenic variant (i.e., carriers) are typically asymptomatic.

Offspring of a proband

• The offspring of an individual with LDLRAP1-related FH are obligate heterozygotes (carriers) for a pathogenic variant in LDLRAP1 (individuals who are heterozygous for an LDLRAP1 pathogenic variant are typically asymptomatic).
• If the reproductive partner of a proband is heterozygous for an LDLRAP1 pathogenic variant, offspring are at risk of inheriting biallelic pathogenic variants and having LDLRAP1-related FH. Genetic counseling and genetic testing can be offered to the reproductive partner to assess this risk.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an LDLRAP1 pathogenic variant.

Related Genetic Counseling Issues

Family-based cascade screening. The CDC has classified FH as a Tier 1 condition, indicating a significant benefit from performing family-based cascade screening. Cholesterol testing, with or without molecular testing in relatives of affected persons with FH, can be used to identify individuals with FH and provide them with lifesaving treatment. Early diagnosis and treatment of relatives at risk for FH can reduce morbidity and mortality [Knowles et al 2017, Sturm et al 2018].

Predictive genetic testing for asymptomatic family members at risk for FH requires prior identification of the pathogenic variant(s) in the family. If the FH-related pathogenic variant(s) in the family are known, it is recommended that all first-degree family members be offered predictive genetic testing.

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• Young women with FH should receive counseling regarding contraindications of lipid-lowering therapies during pregnancy (see Management, Pregnancy Management).
• The proband's reproductive partner should be offered cholesterol screening, followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH. Ideally, this should be offered prior to conception to assess the risk of having a child with HoFH.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the FH-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

LDLR encodes low-density lipoprotein receptor (LDLR), a cell surface protein involved in endocytosis of low-density lipoprotein 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. Pathogenic variants in LDLR usually either reduce the number of receptors produced within the cells or disrupt the ability of the receptor to bind LDL-C, resulting in high levels of plasma LDL-C.

APOB encodes apolipoprotein B-100. APOB pathogenic variants alter the ability of apolipoprotein B-100 to effectively bind LDL-C to LDLR on the cell surface, causing fewer LDL-C particles to be removed from the blood.

The PCSK9 protein product binds to LDLRs and promotes their degradation in intracellular acidic compartments. Pathogenic variants in PCSK9 have been associated both with hypercholesterolemia and hypocholesterolemia. Gain-of-function pathogenic variants cause hypercholesterolemia by excessive degradation of LDLRs, reducing the amount of LDL-C removed from the blood. Loss-of-function pathogenic variants cause hypocholesterolemia (reduced blood cholesterol levels) by increasing the number of LDLRs on the surface of liver cells, resulting in a quicker-than-usual removal of LDL-C from the blood and reduced incidence of coronary artery disease [Cohen et al 2006, Pandit et al 2008].

The LDLRAP1 protein plays an important role in moving LDLRs and their attached LDL particles into the liver cells for recycling. Biallelic loss-of-function LDLRAP1 variants have been the primary disease mechanism reported and inhibit the removal of LDL-C from the blood [D'Erasmo et al 2020].

Author Notes

Dr Knowles is a physician-scientist, and the overall theme of his research is the genetic basis of cardiovascular disease, with contributions across the continuum from discovery to the development of model systems to the translation of these findings to the clinic and most recently to the public health aspect of genetics. Currently his discovery and basic translational efforts center on understanding the genetic basis of insulin resistance using GWAS studies coupled with exploration in model systems including standard cell lines, induced pluripotent stem cells and murine models. These efforts are funded through the NIH. His clinical translational focus is on the intersection of lipids and insulin resistance, particularly defining how statins increase the risk of diabetes (Doris Duke Foundation grant). His clinical role at Stanford is as a lipidologist and director of the Familial Hypercholesterolemia (FH) clinic, where they provide world-class care to individuals with FH and related lipid disorders. His interest in FH has led him to explore innovative ways of addressing the major public health impact of this genetic condition. As the volunteer Chief Medical Advisor of the FH Foundation (a patient-led research and advocacy organization), he led the FH Foundation's efforts to establish a national patient registry for FH (CASCADE FH) and apply for an ICD10 code for FH. He has used cutting-edge "big-data" approaches to identify previously undiagnosed FH patients in electronic medical records (the FIND FH project, partly funded by the AHA).

Hannah Ison is a licensed Cardiovascular Genetic Counselor at the Stanford Center for Inherited Cardiovascular Disease. In her role she primarily specializes in caring for patients and families with inherited dyslipidemias and has been actively involved in efforts to identify and care for individuals at risk for familial hypercholesterolemia (FH) for close to five years. She works with both adult and pediatric patients and has assisted with and managed the development of the Pediatric Lipid Clinic at Stanford Children's Hospital. Additionally, she is a member of the National Society of Genetic Counselors and is co-chair of the Dyslipidemia Working Group through this organization.

Shoa Clarke is a preventive cardiologist and a geneticist. He is boarded in internal medicine, pediatrics, and cardiovascular medicine. He cares for adults, children, and families with genetic risk factors for cardiovascular disease, including familial hypercholesterolemia.

Acknowledgments

The FH Foundation, AHA, NIH, Doris Duke Foundation

Author History

Shoa L Clarke, MD, PhD (2022-present)
Hannah E Ison, MS, LCGC (2022-present)
Joshua W Knowles, MD, PhD (2014-present)
Mitchel Pariani, MS, LCGC; Stanford Center for Inherited Cardiovascular Disease (2016-2022)
Emily Youngblom, PhD, MPH; University of Washington School of Public Health (2014-2022)

Revision History

• 7 July 2022 (sw) Comprehensive update posted live
• 8 December 2016 (sw) Comprehensive update posted live
• 2 January 2014 (me) Review posted live
• 5 August 2013 (jl) Original submission

Published Guidelines / Consensus Statements

• Chora JR, Iacocca MA, Tichý L, Wand H, Kurtz CL, Zimmermann H, Leon A, Williams M, Humphries SE, Hooper AJ, Trinder M, Brunham LR, Costa Pereira A, Jannes CE, Chen M, Chonis J, Wang J, Kim S, Johnston T, Soucek P, Kramarek M, Leigh SE, Carrié A, Sijbrands EJ, Hegele RA, Freiberger T, Knowles JW, Bourbon M, et al. The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genet Med. 2022;24:293–306. [PubMed: 34906454]
• de Ferranti SD, Steinberger J, Ameduri R, Baker A, Gooding H, Kelly AS, Mietus-Snyder M, Mitsnefes MM, Peterson AL, St-Pierre J, Urbina EM. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association. Circulation. 2019;139:e603–34. [PubMed: 30798614]
• DeMott K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical guidelines and evidence review for familial hypercholesterolæmia: the identification and management of adults and children with familial hypercholesterolæmia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. Available online. 2008. Accessed 6-23-22.
• Descamps OS, Tenoutasse S, Stephenne X, Gies I, Beauloye V, Lebrethon MC, De Beaufort C, De Waele K, Scheen A, Rietzschel E, Mangano A, Panier JP, Ducobu J, Langlois M, Balligand JL, Legat P, Blaton V, Muls E, Van Gaal L, Sokal E, Rooman R, Carpentier Y, De Backer G, Heller FR. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, pædiatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218:272–80. [PubMed: 21762914]
• Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Available online. 2011. Accessed 6-28-22.
• 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, et al. 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:S1–8. [PubMed: 21600525]
• Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082–e1143. [PMC free article: PMC7403606] [PubMed: 30586774]
• Hegele RA, Borén J, Ginsberg HN, Arca M, Averna M, Binder CJ, Calabresi L, Chapman MJ, Cuchel M, von Eckardstein A, Frikke-Schmidt R. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol. 2020;8:50–67. [PubMed: 31582260]
• Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, et al. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S9–17. [PubMed: 21600530]
• Ito MK, McGowan MP, Moriarty PM, et al. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S38–45. [PubMed: 21600528]
• Martin AC, Coakley J, Forbes DA, Sullivan DR, Watts GF. Familial hypercholesterolæmia in children and adolescents: a new pædiatric model of care. J Paediatr Child Health. 2013;49:E263–72. [PubMed: 23252991]
• Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, Baum SJ, Bourbon M, Carrié A, Cuchel M, de Ferranti SD, Defesche JC, Freiberger T, Hershberger RE, Hovingh GK, Karayan L, Kastelein JJP, Kindt I, Lane SR, Leigh SE, Linton MF, Mata P, Neal WA, Nordestgaard BG, Santos RD, Harada-Shiba M, Sijbrands EJ, Stitziel NO, Yamashita S, Wilemon KA, Ledbetter DH, Rader DJ. Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72:662–80. [PubMed: 30071997]

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