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Genetic aspects of familial hypercholesterolemia and its diagnosis
1Department of Medicine, University of Washington, Seattle 98195.
Insights
Familial hypercholesterolemia (FH) is a common genetic disorder affecting 1 in 500 people, increasing coronary atherosclerosis risk. Diagnosis can be challenging due to varied symptoms and overlapping lab values.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Familial hypercholesterolemia (FH) is a prevalent genetic disorder affecting 1 in 500 individuals, significantly increasing the risk of coronary atherosclerosis.
- Clinical manifestations of coronary heart disease (CHD) typically appear in the fourth or fifth decade for males and a decade later for females, with interactions from other risk factors like smoking.
- Homozygous and compound heterozygous forms of FH are rare (1 in 1,000,000) and lead to severe hypercholesterolemia, xanthomas, and early-onset CHD.
Purpose of the Study:
- To review the genetic basis, clinical presentation, diagnostic challenges, and molecular diagnostic approaches for familial hypercholesterolemia.
- To highlight the impact of FH on coronary atherosclerosis and the varying age of onset for cardiovascular events.
- To discuss the complexities of FH diagnosis, especially in heterozygotes, and the role of genetic testing.
Main Methods:
- Review of existing literature on familial hypercholesterolemia, focusing on genetic mutations, clinical outcomes, and diagnostic strategies.
- Analysis of population-specific mutation profiles in founder populations.
- Discussion of molecular diagnostic techniques, including direct and indirect DNA testing.
Main Results:
- FH is caused by mutations in the low-density lipoprotein (LDL) receptor gene on chromosome 19, with specific founder mutations prevalent in certain populations.
- Diagnosis of heterozygote FH is often difficult due to absent physical findings and overlapping laboratory values.
- The genetic heterogeneity of FH complicates population-wide DNA screening, though direct or indirect molecular diagnosis is feasible when the specific defect is known or family studies are conducted.
Conclusions:
- Familial hypercholesterolemia is a significant genetic risk factor for premature coronary atherosclerosis, requiring careful clinical and laboratory assessment.
- Despite diagnostic challenges, molecular methods offer precise diagnosis when specific LDL receptor defects are identified or through genetic linkage analysis.
- Understanding the genetic basis and diagnostic complexities of FH is crucial for effective management and prevention of cardiovascular disease.
Abstract:
Heterozygote familial hypercholesterolemia (FH) is a frequent genetic trait (one in 500) that predisposes to coronary atherosclerosis. Male heterozygotes often develop clinical manifestations of coronary heart disease in their fourth or fifth decade, females, about 10 years later. Other risk factors for ischemic heart disease like smoking interact with the gene for FH. Homozygotes and compound heterozygotes (i.e., those who carry two different FH genes) are very rare (one in 1,000,000) have severe hypercholesterolemia with xanthomas, and develop coronary heart disease early in life. FH is caused by one of many different mutations (deletions, insertions, missense, or nonsense mutations) affecting the well-defined low density lipoprotein (LDL) receptor gene on chromosome 19. Some populations that started with a small founder group like the Afrikaners in South Africa and the French Canadians carry only a few FH mutations. The diagnosis of heterozygote FH is often difficult, since physical findings (xanthomas) are frequently absent, and overlap of laboratory test values between affected and nonaffected subjects occurs. The a priori probability of heterozygosity of FH varies from one in 500 in population studies to one in two in family studies and must be considered when assessing borderline quantitative test results based on cholesterol, LDL cholesterol, or LDL-receptor assays. The mutational heterogeneity of FH makes it very difficult to use DNA methodology for population detection. However, direct molecular diagnosis by appropriate DNA probes is possible if the specific LDL receptor defect is known. Indirect molecular diagnosis based on genetic linkage of a common DNA variant of the LDL receptor to the basic defect is often feasible but requires family studies.