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The complex molecular genetics of familial hypercholesterolaemia

Amanda J Berberich¹, Robert A Hegele²

¹Departments of Medicine and Biochemistry, and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Nature Reviews. Cardiology

|July 6, 2018

Insights

Familial hypercholesterolaemia (FH) is a common genetic disorder causing early cardiovascular disease, yet it remains underdiagnosed and undertreated. Understanding its genetic complexity is key to improving diagnosis and patient outcomes.

Area of Science:

Cardiovascular Genetics
Metabolic Disorders
Clinical Lipidology

Background:

Familial hypercholesterolaemia (FH) is the most prevalent genetic disorder linked to premature cardiovascular disease.
A significant proportion of FH patients remain undiagnosed or receive suboptimal treatment.
Recent advancements in molecular technologies are refining our understanding of FH prevalence and its complex genetic underpinnings.

Purpose of the Study:

To highlight the diagnostic challenges and complexities of Familial hypercholesterolaemia.
To emphasize the evolving understanding of FH due to genetic research.
To underscore the importance of elevated LDL cholesterol as a diagnostic and therapeutic trigger.

Main Methods:

Review of current understanding of FH pathophysiology and genetics.
Analysis of diagnostic criteria and the role of genetic testing.
Discussion of clinical features and their diagnostic implications.

Main Results:

FH is a spectrum of disorders, not limited to the classic phenotype.
Genetic testing can be complex and not always definitive for diagnosis.
Elevated LDL cholesterol is the primary indicator, even without classic signs.

Conclusions:

FH diagnosis requires a comprehensive approach, integrating clinical, family, and genetic data.
Elevated LDL cholesterol levels are paramount for initiating management, regardless of other indicators.
Early intervention with lifestyle changes and lipid-lowering therapy is crucial for cardiovascular disease prevention in FH.

Read full analysis

Abstract:

Familial hypercholesterolaemia is the most commonly encountered genetic condition that predisposes individuals to premature cardiovascular disease. Nevertheless, most patients are undiagnosed, and treatment is often suboptimal even when the diagnosis seems certain. Advances in molecular technologies are reshaping our understanding of this condition, including revision upwards of the population prevalence. Furthermore, the underlying pathophysiological complexity has been exposed by the range of causative genetic loci, breadth of types and classes of rare disease-causing variants, and polygenic basis of the phenotype in many patients. Genetic testing is not always helpful or definitive. Familial hypercholesterolaemia can be envisioned as a group of related disorders, of which the classic 'textbook' phenotype is a subset. Features such as clinical stigmata, family history of dyslipidaemia or cardiovascular disease, and presence of a rare pathogenic variant all increase diagnostic certainty. However, even in the absence of these elements, the essential feature remains an elevated level of plasma LDL cholesterol, which alone should prompt a dialogue between the care provider and the patient on lifestyle modification and lipid-lowering therapy as the foundation of a long-term strategy to prevent or delay the onset of cardiovascular disease.

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