Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by abnormally high concentrations of low-density lipoprotein (LDL) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease (CHD) and death. FH is one of the most common inherited disorders and the most common one known to cause premature CHD in people of European descent. The vast majority of people with FH have inherited a single mutation from one parent in either the LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Despite their greatly elevated risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or inadequately treated.
Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family tracing. The National Institute for Health and Clinical Excellence in the United Kingdom recommends cascade screening of close biological relatives of people with a clinical diagnosis of FH in order to effectively identify additional FH patients. The ultimate goal of this testing is to reduce morbidity and mortality from heart disease in persons with FH through early diagnosis and effective disease management. The goal of this article is to outline the available evidence on the clinical validity and utility of cascade screening for FH, while emphasizing the availability, usefulness, and recommendation for including DNA testing (if the disease-causing mutation has been identified).
A patient has been diagnosed with familial hypercholesterolemia (FH). Use cascade screening to identify biological relatives of the patient who are also affected with the disorder.
Identifying and contacting biological relatives of a person diagnosed with FH (the index case) and then systematically testing these relatives (first-, second-, third-, etc. degree) using a combination of serum LDL cholesterol concentration measurements and a variety of mutation detection or screening assays for mutations in the LDLR , APOB , or PCSK9 genes.
Public Health Importance
FH is one of the most common inherited disorders, with an estimated worldwide prevalence of 1 in 500 (0.2%), though the frequency is considerably higher in some populations because of a founder effect  . This estimate corresponds to approximately 13 million people worldwide and ~600,000 in the United States who have FH. The overwhelming majority of affected persons are heterozygotes (those who have inherited one disease-causing mutation). A smaller number of patients (~1 in 200,000) are compound heterozygotes (who have inherited one copy each of two different mutations), while persons with homozygous FH (who have inherited two identical disease-causing mutations) are extremely rare (~1 in 1 million).
The elevated serum cholesterol levels associated with FH lead to a greatly elevated risk for coronary heart disease (CHD) and death  . In fact, for those with heterozygous FH, the cumulative risk for CHD is greater than 50% in men by the age of 50 and at least 30% in women by the age of 60  . Persons with homozygous FH manifest an even more severe form of the disorder. There is variation in the onset and severity of atherosclerotic disease in persons with FH, since environmental, metabolic, and genetic factors influence the clinical phenotype  .
Overall, estimates are that fewer than 25% of persons with FH are diagnosed; and the majority remain untreated or improperly treated  , though there are no recent estimates available for the United States  . (Persons may be treated for high cholesterol without knowledge that they have FH. False-negative diagnoses can result in inadequate treatment, while false-positive diagnoses may result in overtreatment.)
Because of the high prevalence of FH among family members (50% of first-degree relatives of heterozygotes are affected), cascade screening has been shown to be a cost-effective method of identifying people with FH  . Early detection and treatment with statins have been shown to reduce morbidity and mortality among those with heterozygous FH  .
Despite an international effort to improve the identification and management of patients with FH  , few countries have established large-scale programs to systematically determine the FH status of relatives of these patients  .
Published Reviews, Recommendations and Guidelines
Systematic evidence reviews
A systematic evidence review  was conducted during the formulation of guidelines from the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom (see next subsection).
Recommendations by independent group
The NICE guidelines on the identification and management of FH recommend cascade screening using a combination of genetic testing and LDL cholesterol 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”  .
Guidelines by professional groups
Until recently, there were no formal clinical guidelines or recommendations in the United States regarding cascade screening for FH. However, in June 2011, the National Lipid Association issued guidelines strongly encouraging the use of cascade screening to identify persons with FH  . Also in June 2011, the European Society of Cardiology and the European Atherosclerosis Society jointly issued guidelines recommending family screening (and cascade screening, if resources are available) for the detection of FH  . In both of these guidelines, cascade screening does not necessarily incorporate genetic testing, though DNA analysis is noted as being useful in some cases  or is recommended whenever resources are available  .
Analytic Validity : Test accuracy and reliability in measuring the genomic markers of interest— mutations in the LDLR , APOB , or PCSK9genes (analytic sensitivity and specificity).
Clinical Validity : Test accuracy and reliability in identifying relatives of patients with FH (predictive value).
Clinical Utility : Net benefit of cascade screening in improving health outcomes.
- The identification and diagnosis of index cases.It is unclear whether a screening program should be implemented to find FH index cases and, if so, what type of program would be best (e.g., population-based or opportunistic screening of adults; universal or targeted lipid screening of children)  . In addition, three groups have developed diagnostic criteria for FH. These criteria differ in their need for (and the sufficiency of) DNA testing and in their diagnostic effectiveness  .
- The possibility of variation in the severity of FH phenotypes according to the type of mutation (the genotype-phenotype relationship), particularly for LDLR . For example, LDL receptor-null mutations have been associated with higher blood LDL cholesterol levels compared with LDL receptor-defective mutations  . However, family-based and population-based studies have largely found that statin treatment efficacy or the risks of CHD or CHD-related mortality are not affected by LDLR mutation type  . Of note, the only subgroup analysis performed in a randomized, double-blinded trial showed that LDLR mutation type altered the LDL-lowering effect of the investigated statin, but this trend was not statistically significant  .
- Uncertainty surrounding when and how to pharmacologically treat lipid disorders in children.As noted previously, there is no evidence of the long-term health benefits or safety of statin treatment in children, as the longest follow-up period in studies was 2 years  . Therefore, even if a child with FH is identified through cascade screening, the issue of when to start drug therapy is not straightforward. The U.S. Preventive Services Task Force (USPSTF) has not issued specific recommendations for the treatment of children with FH, although it did note that statins are effective for reducing total and LDL cholesterol levels in these children  . The American Academy of Pediatrics recommends that in children and adolescents with heterozygous FH, initial intervention “is focused on changing the diet. However, if this approach does not lower LDL to an acceptable concentration, these children may be candidates for pharmacologic intervention”  . The American Heart Association is more aggressive, recommending the consideration of lipid-lowering therapy for children aged ≥10 years (and after the onset of menses for girls) whose LDL levels are “severely elevated” and that the age or LDL cutpoint at which such therapy is initiated may be even lower for children with additional cardiovascular risk factors  . The National Lipid Association says that consideration should be given to starting treatment in children with (heterozygous) FH at 8 years of age or older  . The recommendation from NICE is similar: “lipid-modifying drug therapy for a child or young person with (heterozygous) FH should usually be considered by the age of 10 years”, taking into account the presence of other cardiovascular risk factors and the family history of CHD  .It is important to note, however, that lifestyle interventions are also an important component of the medical management of FH for both children and adults  , since environmental and metabolic factors can influence the FH phenotype  . FH patients (including children) are encouraged to get adequate physical activity, eat a healthy diet, and to refrain from smoking. Of note, however, a recent Cochrane review of randomized controlled trials found that currently available data are insufficient to reach any conclusions regarding the efficacy of different dietary interventions for FH patients, including a lack of data on the usefulness of dietary modification over and above lipid-lowering drug therapy  .
- The best means by which to contact relatives of an FH index case.This subject is currently under debate  .
In summary, the clinical validity and utility of cascade screening for FH is dependent on a number of factors, including the criterion used to diagnose the disorder in the index case, the use of DNA testing in the index case and in relatives, and the nature of the benefit and possible harms of identifying and pharmacologically treating the disorder in childhood. Nevertheless, cascade screening is a straightforward and highly effective way to identify persons who have FH.
Last updated: July 1, 2011
We would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics (OPHG) at CDC for comments and guidance.
This work was supported by the Office of Public Health Genomics (OPHG), Office of Surveillance, Epidemiology, and Laboratory Services (OSELS), Centers for Disease Control and Prevention (CDC).
The authors declare that no competing interests exist.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC).
The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we suggest that you discuss them with your health care provider.
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