**4. Diagnosis**

Since CV risk is related to the cumulative exposure to elevated lipids, early diagnosis is important for earlier treatment of HoFH to reduce CV risk. Although genetic testing can confirm FH, it is not well defined since genetic confirmation can be difficult to verify in some patients [10]. Indeed, genetic testing is generally not needed as the disease is primarily diagnosed via clinical and biochemical features [6–8, 10, 18]. A number of diagnostic criteria have been proposed [8], but they are typically based on family history (i.e., HeFH in both parents and/or premature CAD), the presence of physical manifestations (i.e., tendon xantho‐ mas, corneal arcus) at an early age, severely increased LDL‐C, and molecular diagnosis. Patients with HoFH generally have untreated LDL‐C levels >500 mg/dL (>13 mmol/L) or treated levels ≥300 mg/dL (≥7.76 mmol/L) [8]. However, not all patients (especially children) with HoFH have significantly elevated LDL‐C, with more than one‐half of Dutch children with HoFH having LDL‐C levels between 217 and 379 mg/dL (5.6–9.8 mmol/L) [10]. Patients with a suspected diagnosis of HoFH should typically be referred to a specialized center for proper comprehensive management [6, 10].

Since early detection of patients with HoFH is crucial for the prevention of CVD, targeted and cascade (i.e., identifying family members at risk) screening is recommended for the identifi‐ cation of new cases in adults [6, 7, 16, 19, 20]. Targeted screening to identify index cases is recommended for patients with hypercholesterolemia and at least one of the following features: personal/family history of xanthomas or premature CVD or family history of significant hypercholesterolemia or sudden premature cardiac death [6, 7]. Specific criteria in Europe (i.e., European Atherosclerosis Society [EAS]) are similar, but somewhat different than those of the National Lipid Association in the United States (US), with slightly different cholesterol cut‐points for screening [21]. Such testing is important because most patients identified via screening were not aware of the diagnosis and were therefore not receiving therapy [17]. The index subject should be referred for genetic screening and a family pedigree should be created to identify potential cases, followed by cascade screening with LDL‐C measurements [7]. Targeted screening is also recommended in children and adolescents with CV risk factors [6, 16]. Prenatal diagnosis is possible, and it is recommended that the partners of known cases of HeFH should be tested to exclude the disease [22]. Economic modeling has shown that comprehensive screening using cholesterol and DNA testing is cost‐effective [19].
