Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically elevated levels of low-density lipoprotein (LDL) cholesterol. LDL cholesterol is often referred to as "bad" cholesterol because high levels can lead to the buildup of cholesterol in arteries, increasing the risk of cardiovascular disease, including heart attacks and strokes. It is a relatively common disorder, with an estimated 1 in 400 people in the general population having hypercholesterolemia. In specific populations such as Ashkenazi Jews, French Canadians, Finns, Africans, and Lebanese, the frequency is considerable, affecting 1 in 67 people.
Familial hypercholesterolemia genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of familial hypercholesterolemia include:
- High Cholesterol Levels: Individuals with FH have significantly elevated cholesterol levels from a young age, often well before adulthood.
- Early Onset of Cardiovascular Disease: Due to the persistently high cholesterol levels, individuals with FH have an increased risk of developing cardiovascular disease at an early age, often in their 30s or 40s.
- Family History: As the name suggests, familial hypercholesterolemia is inherited and tends to run in families. If one parent has FH, there's a 50% chance of passing the condition to each child.
There are two main types of familial hypercholesterolemia:
Heterozygous FH (HeFH): This is the more common form, where a person inherits one copy of the faulty gene from one parent. Individuals with HeFH can still produce some functional LDL receptors.
Homozygous FH (HoFH): In this rare form, a person inherits a faulty gene from both parents. HoFH results in extremely high cholesterol levels and a higher risk of early cardiovascular disease.
FH is typically caused by mutations in genes involved in cholesterol metabolism, such as the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), or the proprotein convertase subtilisin/kexin type 9 gene (PCSK9).
Management of familial hypercholesterolemia involves a combination of lifestyle modifications and medications. Lifestyle changes may include adopting a heart-healthy diet, regular exercise, and avoiding tobacco smoke. Medications such as the cholesterol-lowering drugs statins, are often prescribed to help control cholesterol levels.
Given the genetic nature of FH, early diagnosis is crucial for effective management and risk reduction. Genetic testing can confirm the diagnosis and identify specific mutations. Individuals with a family history of early heart disease or high cholesterol levels should consult with a healthcare professional for proper evaluation, diagnosis, and management. Additionally, family members of individuals with FH may benefit from screening and early intervention.
The interaction between LDL and the LDL receptor (LDLR) is central to regulating plasma cholesterol in humans. The protein that binds LDL is apolipoprotein B100 or APOB-100, the primary ligand for the LDL-C cholesterol receptor. Therefore, APOB-100 mediates the binding of LDL-C to its cellular receptor. Pathogenic variants of the APOB gene alter the ability of the protein to effectively bind LDL to the LDLR, resulting in fewer LDL-C particles being removed from the blood by increasing their concentration in the circulatory stream.
FH related to the genes analyzed by this test, APOB and LDLR, follows an autosomal dominant mode of inheritance; a single copy of a pathogenic variant is sufficient for the disease to develop. Patients with two copies of the same pathogenic variant (homozygotes) have more severe symptomatology, a poorer response to statins, and a worse prognosis than patients with one copy (heterozygotes).
The LDLR gene is altered in more than 50% of cases of FH, and more than 2.000 variants that cause the disease have been described. It can also be caused by variants in the APOB (5-10%), PCSK9 (<1%), LDLRAP1 (<1%), APOE (<1%), and STAP1 (<1%) genes; however, in almost 40% of patients with diagnosed FH the genetic cause is unknown. Given the significant variability in LDL-C levels and clinical characteristics among patients, there may be more variants than are known today that could influence the development of FH.
The c.10580G>A variant (p.Arg3527Gln) is the most frequent APOB variant in FH patients of European ancestry.
The c.1775G>A (p.Gly592Glu) variant in the LDLR gene involves the alteration of a highly conserved amino acid and affects the receptor activity of the protein. It is frequent in patients with FH and has been found in heterozygosis, homozygosis, and compound heterozygosis.
The genetic test of familial hypercholesterolemia analyzes the 9 most frequent pathogenic mutations of the APOB gene plus the 264 most frequent pathogenic mutations of the LDLR gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
