Familial Hypercholesterolemia (FH) is a common inherited disorder of cholesterol metabolism that affects approximately one in 250 people globally, often remaining undiagnosed. The condition is characterized by extremely high levels of low-density lipoprotein (LDL) cholesterol, or “bad cholesterol,” from birth. This lifelong exposure to elevated cholesterol causes plaque to build up in the arteries, significantly accelerating the risk of premature heart disease and stroke. FH is transmitted in an autosomal dominant pattern, meaning a child has a 50% chance of inheriting the condition from an affected parent. Early and accurate detection through systematic testing is important because timely treatment can reduce the risk of cardiovascular events by as much as 80%.
Initial Clinical Diagnosis and Scoring Systems
Testing for Familial Hypercholesterolemia begins with a comprehensive assessment, including a standard blood test known as a lipid panel. The panel measures cholesterol concentration, and an untreated LDL cholesterol level two to three times higher than average strongly suggests FH. For an adult, an LDL-C level consistently above 190 milligrams per deciliter (mg/dL), or 4.9 millimoles per liter (mmol/L), is a significant indicator. For a child, a level over 160 mg/dL (4.1 mmol/L) raises immediate suspicion.
The clinician also conducts a physical examination to look for specific signs of cholesterol accumulation outside the blood vessels. These physical markers can include tendinous xanthomas, which are cholesterol-filled deposits that appear as yellowish lumps, most commonly found in the tendons of the hands, feet, or Achilles tendon. Another suggestive sign is corneal arcus, a white or gray ring around the iris, particularly when observed in a patient under the age of 45.
Gathering a detailed family history is crucial. Since FH is genetic, a documented history of early-onset cardiovascular disease or stroke in first-degree relatives (parents or siblings) is highly suggestive. High cholesterol levels in multiple family members further strengthen the suspicion of an inherited disorder.
To standardize diagnosis, physicians use validated scoring systems that integrate cholesterol levels, physical findings, and family history. The Dutch Lipid Clinic Network (DLCN) Criteria is one such tool, which assigns points to each clinical factor. A patient’s total score then categorizes the likelihood of having the condition as unlikely, possible, probable, or definite FH.
The Simon Broome Register Criteria is another established system, combining specific LDL-C thresholds with physical signs or genetic evidence to define definite or possible FH. These scoring tools help quantify the suspicion of FH and determine the necessity of proceeding to definitive genetic testing. An elevated score often triggers the need for genetic confirmation.
Definitive Genetic Testing
While clinical criteria establish a high probability of FH, genetic testing provides a definitive diagnosis by identifying the pathogenic mutation. Testing is typically performed on a simple blood sample or a cheek swab, from which the patient’s DNA is analyzed. Genetic confirmation is advised when a patient meets the criteria for probable or definite FH.
Testing focuses on three major genes responsible for the vast majority of FH cases. The LDLR gene, which codes for the LDL receptor, is the most common site for a mutation, leading to the liver’s inability to efficiently clear LDL cholesterol from the bloodstream. Mutations in the APOB gene affect the protein component of the LDL particle, preventing it from binding correctly to the receptor.
A third gene tested is PCSK9, where a gain-of-function mutation causes the corresponding protein to prematurely destroy the LDL receptors. Identifying a pathogenic variant confirms the diagnosis, irrespective of the patient’s current cholesterol levels, which may be lowered by medication. Genetic confirmation is important for guiding long-term treatment strategies, including advanced lipid-lowering therapies.
A positive genetic test distinguishes FH from other, non-inherited causes of high cholesterol. This distinction is important because the condition’s genetic nature carries implications for the patient’s family members. Genetic testing is considered the gold standard for diagnosis and is valuable when cholesterol levels are borderline or inconclusive.
Cascade Screening for Family Members
Once a person (the proband) receives a confirmed FH diagnosis, the next systematic step is cascade screening. This public health strategy involves actively tracing and testing the proband’s close biological relatives. The goal is to identify affected family members who are unaware of their genetic risk.
Cascade screening begins with first-degree relatives: parents, siblings, and children of the proband. Because FH is autosomal dominant, each relative has a 50% chance of inheriting the gene mutation. If any individual tests positive, the screening process then “cascades” outward to their own first-degree relatives.
If the proband’s specific FH-causing mutation has been identified, relatives can undergo highly targeted testing. This focused approach is less expensive and faster than full genetic sequencing, as the laboratory only checks for the single, known familial variant. Targeted genetic testing has nearly 100% accuracy in predicting future disease risk in children of a known carrier.
Early identification through cascade screening is important because it allows treatment to begin, often in childhood, before significant arterial damage occurs. This proactive approach ensures that seemingly healthy relatives with the genetic variant can begin interventions immediately. Cascade screening is recognized as the most effective method for reducing premature cardiovascular disease caused by FH in the population.