Genetic Evaluation of Familial Hypercholesterolemia
(High levels of LDL cholesterol)
Cascade family screening can reduce disease burden and unexpected complications
Did you know that…
About 1 in 250 people worldwide have FH, but the diagnosis rate is about only about 10%.
FH runs in families. If one parent has FH, each child has a 50% chance of having FH.
High levels of LDL cholesterol contribute to premature morbidity and mortality from coronary heart disease (CHD).
Early diagnosis and appropriate follow-up can significant reduce the risk of CHD events.
What is Familial Hypercholesterolemia (FH)?
Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterised by high circulating levels of LDL Cholesterol (LDL-C) caused by alterations in lipoprotein metabolism.
Patients with FH have a 20x higher risk of premature cardiovascular diseases as result of high concentrations of LDL-C.
If left untreated, men have a 50% risk of having a heart attack by age 50. Untreated women have a 30% risk by age 60.
Genetic testing increases the patient’s adhesion to therapeutic measures and healthier lifestyles.
What is Familial Hypercholesterolemia (FH)?
FH is caused by mutations mainly in LDLR, PCSK9, APOB, STAP1 and LDLRAP1 genes. Genetic alterations in these genes result in impaired processing of LDL particles, which leads to elevated levels of LDL-C in plasma and consequent deposition in tendons and arteries. More than 90 % of the FH patients present mutations in LDL receptor (LDLR) gene. The second most common cause of FH are mutations in apolipoprotein B (ApoB) gene. The APOB protein maintains the integrity of the LDL particle and functions as ligand to LDLR, thus mediating LDL clearance from circulation. Other causes of FH include mutations in PCSK9, whose encoded protein binds to the hepatic LDL receptor (LDLR) protein preventing its recycling to cell surface by enhancing its intracellular degradation. Early identification and treatment of patients, as well as screening of relatives, helps significantly reduce the risk of premature disease.
Signs and Symptoms
Many patients with FH could be clinically asymptomatic. In the primary care setting, the diagnosis of FH may be easily missed. Patients are commonly only identified after experiencing a cardiovascular event at an unexpected age or as a result of a family member being diagnosed.
Visible symptoms include:
- Cholesterol deposits under the skin or tendons (xanthomas). They are yellow bumps that can be small and hard to see.
- An orange yellowish, flat deposit of cholesterol on the eyelids or under the eyes (xanthelasmas)
- Greyish-white ring of cholesterol around the iris (corneal arcus).
- Heart and blood vessel disease: a heart murmur may be the result of narrowing of the opening of the aortic valve by cholesterol buildup.
Primary and cascade screening of suspected family members with FH have shown clinical utility
To learn more about FH diagnosis and treatment, please see NICE guidelines and ESC/EAS Guidelines for the management of dyslipidaemias.
LipoGene Genetic Test
An actionable test to prevent or reduce FH disease burden
Genetic testing identifies family members that should receive closer medical attention and it is the only way to diagnose the disease before clinical signs and symptoms appear.
The utility of genetic testing is recognised in guidelines related to the management of FH.
LipoGene is suitable to:
Asymptomatic individuals that are at risk due to familial history.
Benefits of LipoGene
LipoGene is a reliable test that evaluates FH genetic risk. It is most relevant for cascade family screening.
Asymptomatic individuals with positive genetic testing can receive proper medical treatment.
A sample of blood or saliva is enough to perform the genetic test.
* with family history of FH or coronary heart disease
** Associated with mutations included in this genetic test panel
WITH DISEASE SYMPTOMS
LipoGene supports medical doctors in the clinical diagnosis by identifying the specific mutation(s) causing FH.
Medical doctors can advise on lifestyle modifications and therapeutics to reduce cardiovascular heart disease or atherosclerosis.
3. Family extensive.
Being a hereditary disease, genetic testing estimates family risk for the family relatives who inherited the genetic mutation(s) associated with the disease.
A patient with a mutation causing FH can have high LDL-cholesterol levels from early age. The evidences strongly suggests that this patients should start treatment early (sometimes even as teenagers) because their risk of developing atherosclerosis and heart disease is higher.
Early diagnosis and appropriate follow-up can reduce patient morbidity and mortality.
For this reason, early diagnosis is relevant!
LipoGene is a novel tool to support clinical diagnosis of Familial Hypercholesterolemia (FH).
Familial Hypercholesterolemia (FH) Genetic Context
FH is a is an inherited disorder of lipid metabolism characterized by premature cardiovascular disease.
Key proteins and genes:
The development of FH is associated with functional changes in key proteins of the LDL metabolism:
LDLR – Low density lipoprotein receptor. Involved in LDL-C binding and internalization.
APOB – Apolipoprotein B, main LDL-C apoprotein component, that acts as a ligand for LDL receptor.
PCSK9 – Protease involved in LDL receptor degradation.
LDLRAP1 – An adapter protein that interacts with LDLR.
STAP1 – An adaptor protein that controls systemic cholesterol levels.
The vast majority of the mutations identified in FH patients are associated with LDLR gene (>90%), while mutations in APOB and PCSK9 genes account for approximately 5% and 1% respectively .
LipoGene Gene Panel
The FH genetic test developed by HeartGenetics includes the evaluation of over 160 genetic variants in:
5 genes associated with FH:
LDLR, APOB, PCSK9, LDLRAP1, STAP1
1 gene associated with cardiovascular risk:
How Genetic variants are selected:
Our research is supported by peer review papers that have been published in the reference journals in the field.
All genetic variants have been validated in reference databases (HGMDP, NCBI-OMIM, NCBI- ClinVar, NCBI-Variation Reporter and Ensembl).
The knowledge in our databases was approved by internationally recognised medical geneticists and cardiologists.
Genetic testing is recommended by several renowned international organizations, such as the European Society of Cardiology, the European Society of Atherosclerosis, NICE and World Health Organization.
According to European Society of Cardiology/European Society of Atherosclerosis:
“For the diagnosis of specific genetic hyperlipidaemias, genotyping of apolipoprotein E (APOE) and of genes associated with FH may be considered. Tools for genetic screening in families with FH are now available and should be used in specialized clinics.” 
“Several methods with different sensitivity and specificity have been developed for the clinical diagnosis of FH, but the ‘gold standard’ is a combination of clinical and biochemical factors and the presence of a detectable disease-causing DNA change, which gives the highest clinical utility.” 
According to National Institute for Health and Care Excellence:
“Cascade testing using a combination of DNA testing and LDL-C concentration measurement is recommended to identify affected relatives of those index individuals with a clinical diagnosis of FH. This should include at least the first- and second- and, when possible, third-degree biological relatives.” 
According to World Health Organization:
“Large scale family screening and genetic testing has shown to be highly effective in identifying currently untreated patients.”
FH diagnosis typically occurs using one of the Dutch Lipid Clinic Network (DCLN), Simon Broome Register (SBR) or Make Early Diagnosis to Prevent Early Death (MEDPED) criteria, each of which requires a different set of patient data.
Diagnosis is currently made using a combination of clinical characteristics such as family history, lipid levels, and genetic testing.
FH diagnosis according to Simon Broome’s criteria
FH diagnosis according to Dutch Lipid Clinic Network criteria
NICE recommends the use genetic testing where the causative mutation in the index case has been identified.
How are LipoGene reports?
LipoGene panel includes all the high-risk mutations associated to FH (up to date scientific knowledge)
Our methodology is targeted to the presence or absence of a specific variant associated to FH.
In technology. Our tests have 99% accuracy. In Knowledge: All evidences are supported by updated scientific knowledge and validated by medical doctors.
All results include supporting information for each genetic variant including scientific references to guide the interpretation of test results.
HeartGenetics reports follow the recommendations from the European Society of Human Genetics 
Contact us here for a report example.
Some selected publications relevant in FH
: Nordestgaard, Børge G., et al. “Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease Consensus Statement of the European Atherosclerosis Society.” European heart journal 34.45 (2013): 3478-3490.
: Wald, David S., Jonathan P. Bestwick, and Nicholas J. Wald. “Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis.” MBJ 335.7620 (2007): 599.
: 2016 ESC/EAS Guidelines for the management of dyslipidaemias. European Heart Journal (2016) 37 (39): 2999-3058
: European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur Heart J (2007) 28 (19): 2375-2414.
: NICE Clinical Guideline 71 – Identification and management of familial hypercholesterolaemia. http://www.nice.org.uk/guidance/CG71
: World Health Organization. Familial hypercholesterolemia—report of a second WHO Consultation. Geneva, Switzerland: World Health Organization, 1999. (WHO publication no. WHO/HGN/FH/CONS/99.2)
The genetics and screening of familial hypercholesterolaemia. J Biomed Sci. 2016; 23: 39.