Familial hypercholesterolemia (FH) is not caused by a chromosomal abnormality. It is a monogenic disorder, meaning it results from a mutation in a single gene rather than a large-scale change to an entire chromosome. Chromosomal abnormalities involve missing, extra, or rearranged chunks of chromosomes (as in Down syndrome or Turner syndrome), while FH is caused by small, specific mutations in one of a few genes that control how your body processes cholesterol.
What Actually Causes FH
FH traces back to mutations in genes that help your liver pull LDL cholesterol (often called “bad cholesterol”) out of the bloodstream. Three genes account for the vast majority of cases:
- LDLR gene: The most common culprit. It provides the blueprint for LDL receptors on liver cells. When this gene is mutated, the liver produces fewer or poorly functioning receptors, so LDL cholesterol builds up in the blood instead of being cleared.
- APOB gene: This gene codes for a protein on the surface of LDL particles that helps them dock with liver receptors. Mutations here mean LDL particles can’t latch onto the receptor properly, even if the receptor itself works fine.
- PCSK9 gene: This gene influences how quickly the liver breaks down its own LDL receptors. Gain-of-function mutations cause the liver to destroy its receptors faster than normal, leaving fewer available to clear cholesterol.
A rarer fourth gene, LDLRAP1, causes an autosomal recessive form of FH. Over 20 mutations in this gene have been identified. Unlike the other three, you need to inherit a defective copy from both parents to develop the condition.
Monogenic vs. Chromosomal: Why It Matters
The distinction between a single-gene mutation and a chromosomal abnormality is more than academic. Chromosomal abnormalities typically affect dozens or hundreds of genes at once and cause wide-ranging developmental issues across multiple body systems. FH, by contrast, is precisely targeted. A single mutation disrupts one step in cholesterol processing while leaving everything else intact. This is why people with FH can appear completely healthy aside from their cholesterol levels, especially early in life.
There is also a polygenic form of FH, where no single gene mutation is responsible. Instead, a person inherits a collection of common genetic variants that each nudge cholesterol slightly higher, and their combined effect mimics the clinical picture of monogenic FH. This form is even further removed from a chromosomal abnormality.
How FH Is Inherited
The three main forms of FH (involving LDLR, APOB, or PCSK9) follow an autosomal dominant inheritance pattern. That means you only need one copy of the mutated gene to develop the condition. If one parent carries the mutation, each child has a 50% chance of inheriting it.
Most people with FH are heterozygous, meaning they inherited one defective copy and one normal copy. This is the more common scenario, affecting roughly 1 in 300 people. The liver still has some working LDL receptors, so cholesterol is elevated but not catastrophically. LDL levels in heterozygous FH typically land around 190 to 300 mg/dL.
Homozygous FH is far rarer, occurring in about 1 in 160,000 to 400,000 people. These individuals inherit a defective gene from both parents, which can result in a near-complete absence of functioning LDL receptors. LDL cholesterol in homozygous FH can reach 500 to 1,000 mg/dL, and cardiovascular complications can appear in childhood or adolescence.
What FH Looks Like
Many people with heterozygous FH have no visible symptoms for decades. The condition often surfaces as an unexpectedly high cholesterol reading on routine bloodwork, or after a premature heart attack prompts investigation. Symptoms, when they do appear, typically emerge between the third and sixth decade of life.
Homozygous FH tends to announce itself much earlier. Physical signs can include tendon xanthomas, which are firm yellowish nodules that form over the Achilles tendon, kneecaps, or the tendons on the backs of the hands. Some people develop yellowish bumps on the elbows, buttocks, or trunk. Another hallmark is arcus cornealis, a grayish-white ring that forms around the edge of the iris. In one documented case, a 12-year-old girl presented with widespread skin lesions up to 6 cm in size along with nodules on both Achilles tendons and visible corneal rings. Xanthomas appearing in children or teenagers strongly suggest a severe form of FH.
How FH Is Diagnosed
Because FH is a gene-level condition rather than a chromosomal one, diagnosis combines cholesterol testing, family history, physical examination, and sometimes genetic testing. Several scoring systems exist, but the Dutch Lipid Clinic Network (DLCN) criteria are widely used. Points are assigned based on LDL cholesterol levels, family history of early heart disease, and physical signs like tendon xanthomas.
An LDL level between 190 and 249 mg/dL earns 3 points on the Dutch scale, while levels above 330 mg/dL earn 8 points. A confirmed mutation in the LDLR gene also scores 8 points. A total score above 8 indicates definite FH, 6 to 7 suggests probable FH, and 3 to 5 marks possible FH. For children under 16, a total cholesterol above 260 mg/dL (or LDL above 155 mg/dL) paired with a confirmed DNA mutation meets the threshold for definite FH under the Simon Broome criteria used in the United Kingdom.
Genetic testing can confirm the diagnosis and identify the specific mutation involved. This is particularly useful for cascade screening, where family members of a diagnosed person are tested to catch the condition early. Since FH follows a predictable inheritance pattern, identifying the mutation in one person allows targeted testing of parents, siblings, and children.