What are genes and what is their role in FH?

A genetic variant is a permanent change in the DNA sequence that makes up a gene. Some genetic variants have been shown to cause disease or play a major role in someone’s health conditions. Some variants can serve a protective health function. Some variants are neutral and have no impact on a person’s health.

Each human genome normally contains many gene variants. For single genes, like the LDL receptor gene, many different variants can cause FH. For the FH causing genes, many different variants have been identified. All of these different variants, if pathologic, lead to the same health condition, FH. Different variants may be associated with different degrees of severity of FH. There are currently over 2,000 variants that are considered to be disease-causing in FH.

Sometimes gene testing reports describe a variant as having unknown significance, also known as VUS. This means there is a variant in the gene, but it is not known if it causes the condition or disease. In the future, research will show if this changes.

How is FH inherited?

FH is almost always caused by a “dominant” gene passed down from parent to child. When someone inherits a dominant gene it usually will express itself and can be passed down to both sons or daughters. In genetics, this is called “autosomal dominant inheritance.” This means that if a person inherits an FH variant from only one parent, he or she will have heterozygous FH (HeFH) and usually will have high LDL-C from birth. If both parents have FH, it is possible for a child to get one gene from each parent, called homozygous FH (HoFH), a rare and particularly aggressive form of FH.

This is why we don’t ever find an individual with FH, but we find a family. Individuals with FH often have a parent and siblings who have FH, and we can find signs of FH in every generation. It is possible, but uncommon, to have a “de novo” variant. This means that the FH gene was not inherited from a parent, but instead appears for the first time in the person carrying the gene.

 

What genetic variants are associated with FH?

At present, most people with heterozygous FH have variants in one of three genes: LDLR gene, APOB gene, and PCSK9 gene. Sometimes, people with FH can have negative genetic testing.

Gene 1Percentage
LDLR gene (low-density lipoprotein receptor)60% – 80%
APOB gene (apolipoprotein B or ApoB)1% – 5%
PCSK9 gene (proprotein convertase subtilisin/kexin Type 9)0% – 3%

The LDLR, APOB, and PCSK9 genes encode proteins that have important roles in regulating the body’s LDL-C level, and when these genes are malfunctioning, the LDL-C levels are usually much higher then normal population.

People often have just one disease-causing variant causing HeFH. Rarely, people may inherit two disease-causing variants in the same gene (HoFH) or they may inherit a combination of disease-causing variants in two different genes (compound heterozygous FH). People who are compound heterozygous for FH often present clinically as having HoFH and can be diagnosed and treated accordingly.

 

Monogenic vs. Polygenic Hypercholesterolemia:
FH is a monogenic disorder, meaning it is caused by one gene affecting the LDL receptor. It is also possible to have high cholesterol caused by a combination of many genes with smaller effects that add up – otherwise known as polygenic hypercholesterolemia, or genes not affecting the LDL receptor.

Not all high cholesterol is caused by FH. About 7% of the adults, or about 1 in 14 people, has an LDL-C level above 190 mg/dL, the point at which FH is suspected. Many of those people will also have a family history of heart disease. But only about .4% of the population, or 1 in 220 people, has FH. People with FH are at higher risk for early cardiovascular disease, due to the lifelong exposure to very high LDL-C. When high cholesterol is not caused by FH, it may be influenced by genes and lifestyle. No matter the cause, high LDL-C is an important risk factor for cardiovascular disease and should be addressed. Treatment should follow current guidelines.

Are all FH variants known?

No. Today, approximately 30-40% of individuals with clinical FH will have a negative test result. A genetic counselor can walk through your results based on your specific history.

The field of genetics is progressing and new research is uncovering gene variants and their impact on LDL-C every day. That is why the FH Foundation firmly believes that people with a clinical diagnosis of FH should always be treated, no matter the genetic test result. If your doctor feels that you have FH, even if your genetic test result is negative, you should still be treated for high cholesterol.

 

Who should get a genetic test for FH?

Getting genetic testing is a personal choice and it should not impact the care that someone receives when they have a clinical diagnosis of FH.

 

Someone might consider genetic testing if:

  • they or a close relative has had high LDL-C, which is defined as untreated LDL-C levels over 190 mg/dL (for adults) or 160 mg/dL (for children and teenagers) while not on any lipid-lowering medications
  • if any first- or second-degree relatives have premature coronary artery disease (heart attack, angina, bypass, stent or premature death) before the age of 55 in males and 65 in females
  • if someone or their first- or second-degree relative has any physical characteristics that may point to FH, such as tendon xanthomas or a corneal arcus.

 

 

Genetic testing can be especially helpful when:

  • The family history is unknown. This might be because of adoption, estrangement, or simply a lack of information.
  • Pre-treatment LDL-C is unknown.
  • A person does not know what their LDL-C was earlier in life. If a person does not know what their LDL-C level was in childhood or earlier adulthood, genetic testing may clarify the diagnosis.
  • The LDL-C level is not as high as 190 mg/dL, but family history suggests FH.

Genetic testing can also be an important tool to assist family screening.

It is important to note that not all individuals with FH present the same or to the same degree. Genetic testing can help provide more information about one’s risk or diagnosis.

1Youngblom E, Pariani M, Knowles JW. Familial Hypercholesterolemia. 2014 Jan 2 [Updated 2016 Dec 8]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.