Penetrance

APOB. Penetrance for FH may be reduced in persons with a heterozygous APOB variant . 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 .

PCSK9

• Penetrance is approximately 90% in persons heterozygous for the (p.Ser127Arg) pathogenic variant .

• Penetrance in persons heterozygous for the pathogenic variant is high, with FH manifesting at a young age .

• Penetrance for other heterozygous PCSK9 variants remains largely unknown .

Source: GeneReviews — "Familial Hypercholesterolemia"

Diagnostic Criteria

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)

• 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)

• LDL-C levels 130 mg/dL (3.4 mmol/L) in those with a first-degree relative with FH

• Total cholesterol levels 230 mg/dL (6 mmol/L)

Source: GeneReviews — "Familial Hypercholesterolemia"

Differential Diagnosis

Genetic conditions with clinical and/or laboratory findings similar to those of familial hypercholesterolemia (FH) are summarized in .

Table 5.

Genetic Disorders with Feature(s) Similar to Those of Familial Hypercholesterolemia

Gene(s) | DiffDx Disorder | MOI | Features of DiffDx Disorder

Similar to FH | Distinguishing from FH

ABCG5

ABCG8

| Sitosterolemia | AR | Xanthomas; susceptibility to early-onset CAD. Some persons may present w/ plasma cholesterol/LDL-C (often presents in childhood). | Hematologic abnormalities (hemolytic anemia, thrombocytopenia, stomatocytes); xanthomas in childhood (particularly in absence of hyperlipidemia in parents); poor response to statins

Source: GeneReviews — "Familial Hypercholesterolemia"

Management Guidelines

Evaluations Following Initial Diagnosis

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

Table 6.

Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Hypercholesterolemia

System/Concern | Evaluation | Comment

Cardiovascular

| Measurement of pre-treatment lipid values when possible: TC, LDL-C, HDL-C, triglycerides, lipoprotein(a) |

Consultation w/lipid specialist or clinician w/expertise in FH |

Consider noninvasive imaging modalities (e.g., measurement of carotid intima-media thickness) to help inform treatment decisions, esp in those w/HoFH or AR FH. | Recommended in some guidelines1

Eval for concurrent illnesses (kidney disease, obstructive liver disease, acute myocardial infarction, hypothyroidism) that can affect lipid values |

Genetic

counseling | By genetics professionals2 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of FH to facilitate medical personal decision making

AR = autosomal recessive; FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; HoFH = FH resulting from biallelic (homozygous or compound heterozygous) pathogenic variants in APOB, LDLR, or PCSK9; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance; TC = total cholesterol

1.

Source: GeneReviews — "Familial Hypercholesterolemia"

Clinical Guidance

The following should be avoided:

• Smoking

• High intake of saturated and trans unsaturated fat

• Sedentary lifestyle

• Obesity

• Hypertension

• Type II diabetes mellitus

Source: GeneReviews — "Familial Hypercholesterolemia"

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.

Source: GeneReviews — "Familial Hypercholesterolemia"

Surveillance Guidelines

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 .

Additional recommended evaluations include those in .

Table 8.

Recommended Surveillance in Individuals with Familial Hypercholesterolemia

System/Concern | Evaluation | Comment

Cardiovascular

| Measurement of lipid levels: TC, LDL-C, HDL-C, triglycerides, lipoprotein(a) | • In children: Begin at age 2 yrs monitor closely. At a minimum reassess cholesterol levels between age 9-11 yrs.1Some experts advocate for screening children for lipoprotein(a), but this practice is not universal.1,2

• In adults: The interval of follow-up testing TBD by care team based on presence of other risk factors

Consider noninvasive imaging modalities (e.g., measurement of carotid intima-media thickness) to help inform treatment decisions. | In children: Currently, the routine use of imaging (e.g., measurement of carotid intima-media thickness) is not recommended.

Identify modifiable risk factors: smoking, sedentary behavior, hypertension, diabetes, obesity. |

Source: GeneReviews — "Familial Hypercholesterolemia"