Familial Hypercholesterolemia (FH) is an inherited condition causing unusually high levels of low-density lipoprotein (LDL) cholesterol from birth. This elevated cholesterol accumulates in arteries, increasing the risk of early cardiovascular diseases like heart attacks and strokes. Many individuals with FH remain undiagnosed.
Genetic Mutations Versus Chromosomal Abnormalities
A genetic mutation is a change in the DNA sequence within a single gene. This alteration can be minor, like a single “letter” change, or involve the removal, addition, or rearrangement of a few DNA building blocks. Such changes disrupt a gene’s instructions for making a protein, potentially affecting its function. These mutations are permanent and can be passed down through generations if they occur in germline cells.
In contrast, a chromosomal abnormality is a larger-scale change involving the number or structure of entire chromosomes. Humans typically have 46 chromosomes in 23 pairs. Abnormalities can include too many or too few chromosomes, like in Down syndrome where there’s an extra copy of chromosome 21, or significant rearrangements like deletions or duplications of segments. These extensive changes often affect many genes simultaneously.
Familial Hypercholesterolemia is caused by a genetic mutation, not a chromosomal abnormality. It results from a permanent alteration in the DNA sequence of one or more genes.
Specific Genes Implicated in FH
Familial Hypercholesterolemia primarily stems from mutations in genes responsible for processing LDL cholesterol.
The most common cause, accounting for 80-85% of cases, is a mutation in the LDLR gene. This gene codes for the low-density lipoprotein receptor, found on liver cells, which binds to and removes LDL particles from the bloodstream. When mutated, the liver produces fewer functional LDL receptors, or they cannot effectively clear LDL from the blood. This leads to LDL cholesterol buildup, increasing early heart disease risk.
Another implicated gene is APOB, which provides instructions for making apolipoprotein B. Apolipoprotein B-100 is a key component of LDL particles that binds to the LDL receptor. Mutations in APOB can alter this binding site, preventing LDL particles from attaching properly to their receptors. This means LDL cholesterol remains in circulation, contributing to high blood levels. APOB mutations are found in about 5-7% of FH patients.
The PCSK9 gene is also associated with FH, accounting for less than 5% of cases. This gene produces PCSK9, a protein regulating LDL receptors on liver cell surfaces. PCSK9 typically binds to LDL receptors and promotes their degradation, reducing the liver’s ability to clear LDL. Gain-of-function mutations in PCSK9 lead to an overactive protein, causing excessive degradation of LDL receptors and higher LDL cholesterol levels.
A rarer cause involves mutations in the LDLRAP1 gene, accounting for less than 1% of cases. This gene provides instructions for a protein that helps move LDL receptors and their bound LDL particles from the cell surface into the cell’s interior. Mutations in LDLRAP1 result in a non-functional protein, meaning cholesterol cannot be efficiently transported into the cell for processing. This leads to cholesterol accumulation in the bloodstream.
Inheritance Patterns of FH
Familial Hypercholesterolemia is primarily inherited in an autosomal dominant pattern. This means an individual needs to inherit only one copy of a mutated gene from one parent to develop the condition. If a parent has FH, each child has a 50% chance of inheriting the altered gene and developing FH.
The most common form, heterozygous FH (HeFH), occurs when a person inherits one mutated gene copy. Individuals with HeFH experience significantly elevated LDL cholesterol levels from birth, increasing their risk of coronary artery disease prematurely. HeFH is relatively common, affecting about 1 in 200 to 1 in 250 people.
A much rarer and more severe form is homozygous FH (HoFH), which develops when an individual inherits two copies of the mutated gene, one from each parent. HoFH is considerably less common, with an estimated prevalence of about 1 in 160,000 to 1 in 1,000,000 people worldwide. Those with HoFH have extremely high LDL cholesterol levels, leading to severe cardiovascular disease that can manifest in early childhood. Untreated HoFH can be life-threatening, with severe complications often appearing before age 20 or 30. While most FH cases follow autosomal dominant inheritance, a small percentage, specifically those caused by LDLRAP1 mutations, are inherited in an autosomal recessive manner, requiring two mutated gene copies.
Identifying the Genetic Cause of FH
Diagnosing Familial Hypercholesterolemia often begins with a thorough assessment of family history. A strong family history of very high cholesterol levels or early heart disease in close relatives can be a significant indicator. Healthcare providers also look for physical signs like cholesterol deposits in the skin (xanthomas) or around the eyes (xanthelasmas), and a gray or white ring around the iris (corneal arcus).
Clinical diagnostic criteria, such as the Simon Broome and Dutch Lipid Clinic Network (DLCN) criteria, are widely used to assess the likelihood of FH. These criteria incorporate a point system based on factors like LDL cholesterol levels, physical signs, and family history of high cholesterol or premature coronary heart disease. For instance, the Dutch Lipid Clinic Network criteria assign points for specific LDL-C levels, the presence of tendon xanthomas, and premature cardiovascular disease in the patient or their relatives.
While clinical criteria can strongly suggest FH, genetic testing provides a definitive diagnosis by identifying a mutation in one of the implicated genes (LDLR, APOB, PCSK9, or LDLRAP1). Genetic testing can confirm FH in about 60-80% of suspected cases. This testing is particularly valuable for “cascade screening,” allowing other first-degree relatives to be tested for a specific mutation once identified in one family member. Early identification of FH allows for prompt and aggressive management, significantly reducing the risk of severe cardiovascular complications.