Familial hypercholesterolemia (FH) follows an autosomal dominant inheritance pattern, meaning you only need to inherit one copy of the mutated gene from one parent to have the condition. A parent with FH has a 50% chance of passing it to each child. In rare cases, a different form of FH follows an autosomal recessive pattern, requiring a mutated gene from both parents.
How Autosomal Dominant Inheritance Works
FH is caused by mutations in genes that control how your body clears LDL cholesterol (the “bad” cholesterol) from your bloodstream. The three genes most commonly involved are LDLR, APOB, and PCSK9. Each plays a role in the system your cells use to grab LDL particles and remove them from circulation. When one of these genes carries a mutation, that system doesn’t work properly, and LDL builds up in the blood.
“Autosomal dominant” means two things. First, the gene sits on a regular chromosome (not a sex chromosome), so FH affects men and women equally. Second, only one defective copy of the gene is enough to cause the condition. You don’t need to inherit the mutation from both parents. This is what makes FH so common compared to recessive genetic disorders: every generation in an affected family typically has members with high cholesterol and early heart disease.
Heterozygous FH vs. Homozygous FH
The severity of FH depends on whether you inherit one or two copies of the mutated gene.
Heterozygous FH (HeFH) is far more common. A person with HeFH has one normal gene copy and one mutated copy. Their LDL cholesterol levels are roughly double the normal range. Without treatment, they may experience their first cardiovascular event as early as their thirties. Each of their children has a 50% chance of inheriting the condition.
Homozygous FH (HoFH) occurs when a child inherits a mutation from both parents, both of whom typically have HeFH. This is much rarer and far more severe. LDL cholesterol levels in HoFH are about four times normal, and cardiovascular complications can appear in the first decade of life. Every child of someone with HoFH will inherit at least one mutated copy, meaning all of them will have HeFH at minimum.
There’s also a distinction called compound heterozygosity, which happens when someone inherits two different FH-causing mutations, either in the same gene or in two different FH-related genes. The result is clinically similar to homozygous FH. If both parents carry a mutation in an FH-related gene (even in different genes), their children are at risk of inheriting two mutations and developing severe FH.
The Rare Recessive Form
A small number of FH cases follow autosomal recessive inheritance, caused by mutations in a gene called LDLRAP1. More than 20 different mutations in this gene have been identified. Unlike the dominant form, you need two defective copies (one from each parent) to develop the condition. Carriers who have just one mutated copy of LDLRAP1 are typically asymptomatic.
When both parents are carriers of an LDLRAP1 mutation, each child has a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of inheriting no mutation at all. This recessive form can appear to “skip” generations because carriers show no symptoms, making it harder to trace through a family tree.
Why the Mutation Type Affects Severity
Not all FH mutations are created equal. Researchers have classified LDLR gene mutations into five categories based on what goes wrong with the LDL receptor protein. Some mutations (called null alleles) prevent the cell from making any receptor protein at all. Others allow the protein to be made but block its transport to the cell surface, prevent it from binding LDL, stop it from being pulled inside the cell, or keep it from recycling back to the surface after use.
This matters because the type of mutation shapes how much residual cholesterol-clearing ability your cells retain. Someone who is heterozygous for a null mutation will have only fully functional receptors on their cell surface (from the normal gene copy), with none from the mutated copy. Someone heterozygous for a partially defective mutation will have a mix of working and malfunctioning receptors. In homozygous cases, a total absence of functional receptors produces the most severe disease, while mutations that leave some partial receptor function result in somewhat lower (though still dangerously high) cholesterol levels.
What This Means for Family Screening
Because FH is dominantly inherited, identifying one person in a family opens the door to finding many others. This process, called cascade screening, starts with the diagnosed individual and moves outward to first-degree relatives: parents, siblings, and children. If an affected parent is identified, screening extends to that parent’s siblings and their children. Each relative found to have FH triggers another round of testing among their own close family members.
Cascade screening uses cholesterol testing, genetic testing, or both. It’s particularly effective for FH because the 50/50 odds per child mean roughly half of first-degree relatives of someone with HeFH will also be affected. Many of these relatives have no idea their cholesterol is dangerously elevated, since FH rarely causes symptoms until cardiovascular damage has already begun. Identifying and treating affected children early is especially important, as lifestyle changes and medication started in childhood can significantly alter their long-term cardiovascular risk.
Inheritance Odds at a Glance
- One parent with HeFH, other parent unaffected: each child has a 50% chance of having FH.
- Both parents with HeFH: each child has a 25% chance of homozygous FH, a 50% chance of heterozygous FH, and a 25% chance of being unaffected.
- One parent with HoFH: all children will have at least heterozygous FH.
- Recessive form (both parents are LDLRAP1 carriers): each child has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither mutation.