Familial hypercholesterolemia [12 genes]

Familial hypercholesterolemia (FH) is a hereditary disease characterized by elevated LDL-C levels, early atherosclerosis, and increased early cardiovascular morbimortality. It constitutes one of the most prevalent hereditary diseases (around 1:250 in most populations), and it has been recognized as a global healthcare issue by the WHO.

FH accounts for approximately 9% of cardiac arrests in individuals younger than 65 years and up to 20% of cardiac arrests in individuals younger than 45 years. Early diagnosis and starting on efficient LDL-C-lowering therapies can significantly delay the occurrence of cardiovascular events and even normalize life expectancy.

It is a genetic disease that may be caused either by a point mutation in a single gene (monogenic FH) that results in deficient LDL-C removal from the bloodstream or by the cumulative effects of several polymorphisms (polygenic FH), where each one causes a slight increase in LDL-C levels. Between 20% and 40% of patients diagnosed with clinically defined FH do not show any causative mutations in the classic candidate genes for FH. These individuals may have an unknown polygenic, environmental, or monogenic cause for their hypercholesterolemia. It is estimated that in over 80% of patients with negative genetic tests, a polygenic cause is the most likely explanation for their hypercholesterolemia. To add more complexity, polygenic and monogenic causes of FH are not mutually exclusive entities; on the contrary, they interact, and a polygenic contribution may occur in monogenic FH patients.

Our panels are aligned with the latest recommendations from international organizations, guidelines from expert working groups, and national and international expert consensus documents: European Society of Cardiology (ESC), European Atherosclerosis Society (EAS), HF Expert Panel of the Journal of the American College of Cardiology (JACC), National Lipid Association (NLA), Spanish Atherosclerosis Society (Sociedad Española de Arteriosclerosis, SEA), American Heart Association (AHA), ClinGen Expert Panels, International Society for Pediatric and Adolescent Diabetes (ISPAD), World Health Organization (WHO), Food and Drug Administration (FDA), and National Institute for Health and Care Excellence (NICE).

Characterizing the genetic component of FH is essential, since the prognosis and, therefore, the clinical management of the patient can substantially differ from those of non-genetic hypercholesterolemias. Likewise, it is relevant to determine whether a patient’s FH has a monogenic or polygenic etyology, as cardiovascular risk differs between both groups. This information has major implications for the management of patients and their families.

1. Heterozygous familial hypercholesterolemia: 1:250 for most populations.
2. Homozygous familial hypercholesterolemia: 1:240,000 (estimated)
3. Autosomal recessive familial hypercholesterolemia: < 1:1,000,000
4. Sitosterolemia: < 1:1,000,000
5. Lysosomal acid lipase deficiency: 1:177,000

The identification of causative variants confirms the monogenic FH diagnosis according to the current diagnostic criteria, such as the UK Simon Broome FH register, the Dutch Lipid Clinic Criteria, and the WHO-MEDPED criteria, all of them widely used for the diagnosis of this disease. Recent epidemiological studies have demonstrated that genetic testing for FH is highly cost-efficient and contributes to reducing long-term healthcare spending.

This study is indicated by multiple international scientific communities and working groups on the subject and has been integrated into population-wide detection programs in different countries. Genetic testing is considered the gold standard for FH diagnosis. Several studies have demonstrated a prognostic value according to which, for any given LDL-C level, an individual with a positive genetic test has a higher risk of cardiovascular disease than one with a negative genetic test. Once a mutation has been identified in the proband, it is essential to initiate family screening, including pediatric members, in whom the benefits of early diagnosis and therapeutic intervention have been demonstrated.

The genes selected for this test allow diagnosing HF, as well as differential diagnosis with other hereditary diseases.

Aimed at patients with suspected familial hypercholesterolemia according to current and properly validated clinical criteria.

Capture-based panel sequencing allows increasing diagnostic performance:

• Higher coverage and sequencing depth.
• Higher CNV resolution.
• Customization of known regions of interest not studied by exome testing.