Familial hypercholesterolemia (FH) is inherited in an autosomal dominant pattern, meaning a child needs only one copy of the altered gene from one parent to develop the condition. If one parent has FH, each child has a 50% chance of inheriting it. This single-gene inheritance makes FH one of the most common genetic disorders, affecting roughly 1 in 300 people worldwide.
How Autosomal Dominant Inheritance Works
Every person carries two copies of each gene, one from each parent. In autosomal dominant conditions like FH, a single altered copy is enough to cause high cholesterol from birth. The “autosomal” part means the gene sits on a non-sex chromosome, so FH affects men and women equally.
In practical terms, the math is straightforward. If your mother or father has FH, you have a coin-flip chance of inheriting the altered gene. If you did inherit it, each of your children faces the same 50% odds. This is why FH tends to run visibly through families, often affecting multiple generations in a direct line.
The Three Genes Involved
FH traces back to mutations in one of three genes, each playing a different role in how your body clears LDL cholesterol (the “bad” cholesterol) from the bloodstream.
- LDLR gene: This gene provides the blueprint for LDL receptors on liver cells. These receptors grab LDL particles from the blood and pull them into the liver for disposal. Mutations here are by far the most common cause of FH, resulting in too few receptors or receptors that don’t work properly.
- APOB gene: This gene codes for a protein on the surface of LDL particles that helps them dock onto LDL receptors. When this protein is defective, LDL particles can’t latch on to receptors efficiently, so they stay circulating in the blood.
- PCSK9 gene: This gene controls how quickly LDL receptors are broken down. Certain mutations cause receptors to be destroyed faster than normal, leaving fewer available to clear LDL from the bloodstream.
All three mutations produce the same end result: LDL cholesterol builds up in the blood because the body can’t remove it at a normal rate.
One Copy vs. Two Copies
The severity of FH depends on whether you inherit one altered gene copy or two.
Heterozygous FH (one copy) is the common form. People with heterozygous FH typically have total cholesterol levels in the 350 to 550 mg/dL range, roughly two to three times higher than normal. Without treatment, men with this form face a 50% chance of developing coronary heart disease by age 50. For women, the risk is about 30% by age 60.
Homozygous FH (two copies) is rare and far more severe. This happens when a child inherits an altered gene from both parents, each of whom has FH. Total cholesterol levels in homozygous FH can reach 650 to 1,000 mg/dL. Atherosclerosis develops during childhood, and heart disease can appear before age 20. Visible signs often emerge early: yellow cholesterol deposits (xanthomas) on the knuckles, elbows, knees, Achilles tendons, and buttocks, along with a white-grey ring around the cornea of the eye called corneal arcus.
The Rarer Recessive Form
A less common type of FH follows a different inheritance pattern entirely. Mutations in a gene called LDLRAP1 cause an autosomal recessive form, meaning a child must inherit an altered copy from both parents to be affected. Each parent carries one defective copy without showing symptoms themselves. When two carriers have a child, there’s a 25% chance that child will have the condition.
The LDLRAP1 protein helps LDL receptors transport cholesterol particles into liver cells. Without it, receptors can still bind to LDL in the bloodstream but can’t pull the particles inside for processing. The result is the same dangerous cholesterol buildup, with deposits forming in the skin, tendons, and coronary arteries over time. More than 20 different mutations in this gene have been identified.
Why Prevalence Estimates Have Changed
For nearly four decades, medical textbooks listed heterozygous FH as affecting 1 in 500 people. That figure was never based on population screening. It was mathematically derived from just 10 cases of homozygous FH observed in London out of a population of 10 million, then plugged into a genetics equation. Large meta-analyses using actual population data have since revised the global prevalence to about 1 in 300.
Certain populations carry the condition at even higher rates due to a founder effect, where a small ancestral group passed the mutation through generations with less genetic mixing. Among French Canadians, for example, prevalence is as high as 1 in 80.
How Families Get Tested
Because FH follows a predictable inheritance pattern, diagnosing one person in a family opens the door to finding others. This process, called cascade screening, starts with an identified case and works outward through first-degree relatives: parents, siblings, and children.
Screening typically involves a simple blood test to measure LDL cholesterol levels. Genetic testing can confirm a diagnosis but isn’t always necessary. For children with a family history, guidelines recommend checking cholesterol levels by age 10 at the latest, with earlier testing for suspected homozygous FH. In cases where a child has no symptoms at all and the diagnosis would rely solely on genetic testing, some guidelines suggest waiting until the child is old enough to participate in the decision.
Relatives who don’t share the same doctor are usually encouraged to get their own LDL levels checked at their local practice. The goal is straightforward: the earlier FH is identified, the sooner treatment can begin lowering cholesterol and reducing the long-term risk of heart disease. Since cholesterol damage to arteries accumulates over a lifetime, the years between diagnosis and first treatment matter enormously.