Familial Hypercholesterolemia (FH) is a common genetic condition marked by extremely high levels of low-density lipoprotein cholesterol (LDL-C) from birth. This elevated cholesterol significantly increases the risk of early heart disease. Understanding the precise genetic cause of FH is important for accurate diagnosis and management, particularly whether it stems from a chromosomal abnormality or a genetic mutation.
Understanding Genetic Changes
A genetic mutation involves a change in the DNA sequence of a single gene. These alterations can be as small as a single nucleotide substitution, or they can involve the insertion or deletion of a few nucleotides. Such changes can alter the instructions for making a specific protein, potentially affecting its function or leading to its absence.
In contrast, a chromosomal abnormality represents a much larger-scale change in the genetic material. These abnormalities involve alterations in the number or structure of entire chromosomes. Examples include having an extra or missing chromosome, such as in Down syndrome (Trisomy 21), or large deletions or duplications of chromosomal segments. Mutations affect individual genes, while chromosomal abnormalities involve whole or significant parts of chromosomes.
The Genetic Basis of FH
Familial Hypercholesterolemia is caused by a genetic mutation, not a chromosomal abnormality. This condition arises from specific changes within single genes that play a role in the body’s ability to process and remove LDL cholesterol from the bloodstream. More than 2,000 different mutations have been identified that can lead to FH.
The most frequent cause of FH involves mutations in the LDLR gene, which accounts for the vast majority of cases. Other genes less commonly implicated include APOB (apolipoprotein B), PCSK9 (proprotein convertase subtilisin/kexin type 9), and LDLRAP1 (low-density lipoprotein receptor adaptor protein 1).
Impact of the Mutation on Cholesterol
Mutations in the LDLR gene lead to a deficiency or dysfunction of low-density lipoprotein receptors on liver cells. These receptors bind to circulating LDL particles, facilitating their removal into the liver. When the LDLR gene is mutated, fewer functional receptors are produced, or they cannot effectively bind and internalize LDL. This impaired removal causes LDL cholesterol to accumulate to very high levels in the bloodstream.
Mutations in the APOB gene affect apolipoprotein B-100, a protein component of LDL particles necessary for LDL to bind to the LDL receptor. When APOB is mutated, LDL particles cannot properly attach to receptors, leading to their accumulation. Certain mutations in the PCSK9 gene can also cause FH by enhancing the degradation of LDL receptors, reducing their numbers on liver cell surfaces. Mutations in LDLRAP1 affect a protein that helps transport LDL receptors, resulting in fewer receptors available to clear LDL.
Inheriting Familial Hypercholesterolemia
Familial Hypercholesterolemia is predominantly inherited in an autosomal dominant pattern. An individual only needs to inherit one copy of the mutated gene from one parent to develop the condition. If a parent has FH, there is a 50% chance that each child will inherit the mutated gene and thus the condition.
A rarer and more severe form, homozygous FH, occurs when an individual inherits two copies of the mutated gene, one from each parent. This typically results in much higher cholesterol levels and more aggressive heart disease that manifests at a very young age. While most cases follow the autosomal dominant pattern, some mutations, particularly in the LDLRAP1 gene, can lead to an autosomal recessive form where two mutated copies are needed for the condition to appear.