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Even though the prevalence of familial hypercholesterolaemia is one out of 140 Singaporeans, it is often underdiagnosed. Find out when general practitioners should suspect the genetic condition so that timely treatment can be initiated – a make-or-break factor in lowering associated cardiovascular disease morbidity and mortality for this at-risk group.
Familial hypercholesterolaemia (FH) is one of the most common genetic disorders, with a global prevalence of one in 313 people. It is even more common in Singapore, where the estimated prevalence is one in 140 people.
FH leads to elevated levels of low-density lipoprotein cholesterol (LDL-C), often referred to as ‘bad cholesterol’.
Patients with FH develop high LDL-C from young, and this prolonged exposure to elevated LDL-C places them at a much higher risk (up to 20-fold) of developing cardiovascular (CV) diseases such as heart attacks, angina and peripheral artery disease compared to the general population.
In addition, patients with FH suffer from CV disease at a much younger age. Studies have shown that the average age for a heart attack in men with FH is 50 years (compared to 66 years in those without FH), and in women with FH, it is 60 years (compared to 72 years in those without FH).
Fortunately, the risk of CV disease in individuals with FH can be significantly reduced by diagnosing them early and starting the appropriate treatment.
FH is often underdiagnosed because it is a silent disease, often lacking noticeable signs or symptoms. In many cases, FH is only identified after a premature CV event such as a heart attack. The goal, however, is to diagnose FH early, allowing for primary prevention before adverse events occur.
FH should be suspected in the general population if they have any of the following:
Diagnostic tools like the Simon Broome criteria (Table 1) or the Dutch Lipid Network criteria (Table 2) incorporate these factors and can help to diagnose FH in clinical practice.
Lifestyle modifications such as a heart-healthy diet, regular exercise and smoking avoidance remain the cornerstone of CV risk reduction for all individuals. However, in those with FH, these measures alone are inadequate to lower LDL-C and prevent CV events, making pharmacological intervention necessary.
Initiating treatment early has consistently been Proven to reduce LDL-C levels from the outset and significantly lower the associated CV morbidity and mortality with FH.
Pharmacological treatment
First-line treatment in primary care
Statins are the first line of treatment, and depending on response and tolerance, additional non-statin agents like ezetimibe may be needed. These therapies are available in the primary care setting.
Additional therapeutic options
For individuals whose LDL-C levels remain above target despite the above, additional therapeutic options include:
Bile acid sequestrants (e.g., cholestyramine)
PCSK9 inhibitors (e.g., evolocumab, alirocumab)
Small interfering RNA molecules (e.g., inclisiran)
Adenosine triphosphate citrate lyase inhibitors (e.g., bempedoic acid)
Plasmapheresis (a procedure to selectively remove LDL-C from the bloodstream)
Treatment targets (in adults)
Primary prevention
FH without other risk factors, aim for LDL < 2.6 mmol/L (< 100 mg/dL)
FH with other risk factors (e.g., diabetes, smoking, hypertension, age > 40 years), aim for LDL < 1.8 mmol/L (< 70 mg/dL)
Secondary prevention
FH with established atherosclerotic CV, aim for LDL < 1.4 mmol/L (< 55 mg/dL)
Inheritance pattern
FH is a monogenic disorder that is inherited in an autosomal dominant (AD) pattern in most cases. This means a person may develop high cholesterol if they inherit one defective gene from a parent. The majority of patients with FH have a single gene mutation (i.e., heterozygous) and there is a 50% chance of passing the gene to their offspring.
Presence of a genetic mutation
In 60-80% of individuals who meet the clinical criteria for ‘definite’ FH, a mutation is found in one of the three key genes: LDLR, ApoB, and PCSK9. However, genetic testing does not detect all cases of FH. Therefore, the absence of a genetic mutation does not exclude FH in patients with a high clinical suspicion.
On the other hand, individuals with a diagnosis of clinical FH and positive test for a FH-linked genetic mutation have an increased risk of CV events compared to those without a mutation.
This underscores the prognostic significance of genetic status in FH.
While genetic testing is not mandatory to diagnose FH, it has incremental value in the detection of FH, owing to the reduced sensitivity of clinical diagnostic criterion.
When FH genetic testing yields a positive result, it offers several key insights:
Confirms clinical FH diagnosis and aids in prognosis
Informs LDL-C treatment thresholds and intensification, especially in primary prevention
Has been shown to increase initiation and adherence to pharmacological therapy
Facilitates identification of at-risk family members through predictive testing, allowing early intervention
In the broader healthcare framework, with a focus on preventative care in Singapore through the Healthier SG and National Precision Medicine initiatives, genetic testing in FH serves a crucial role.
The early identification of high-risk individuals and early intervention opportunities in FH, through greater collaboration between primary care and specialists, is poised to reduce the burden of CV disease at a national scale.
How is genetic testing performed?
Genetic testing for FH is done through a simple blood draw or buccal swab. Next-generation sequencing (NGS) is used to detect mutations in genes commonly associated with FH.
Possible outcomes
The possible outcomes of FH genetic testing include:
Positive: A known mutation in an FH-related gene is identified, conferring the above stated benefits.
Negative: No variants are identified in the FH-related genes tested.
Variant of uncertain significance (VUS): Variants are identified in FH-related genes but their significance in FH causation is not clear.
Interpretation of results
A negative or VUS result does not exclude the possibility of a genetic cause for FH, and management is guided by clinical factors. Further testing may be considered in selected cases.
Role of counselling
Genetic testing should always be accompanied by pre- and post-testing counselling by qualified professionals. This ensures that patients understand the implications of genetic testing results and their potential impact on their health, insurance and relatives.
While dyslipidaemia can be effectively managed in primary care, specific considerations that warrant a referral or collaboration with a specialist include:
Genetic counselling and testing in individuals with a high suspicion of FH based on clinical diagnostic criteria
Genetic counselling and testing in relatives of individuals with known FH
Consideration of second-line lipid-lowering therapy due to suboptimal LDL-C reduction, despite being on maximum tolerated first-line statin and non-statin therapies and adequate lifestyle modifications
Cardiovascular Genetics Service at NHCS
The National Heart Centre Singapore (NHCS) offers a dedicated Cardiovascular Genetics (CVG) Service integrating cardiologists, geneticists and genetic counsellors. This collaboration ensures comprehensive support for patients and their families throughout their genetic testing journey and beyond.
The recent establishment of in-house genetic testing at NHCS in collaboration with KK Women’s and Children’s Hospital (KKH) has:
Enhanced communication between the clinical and laboratory teams
Enabled interpretation of genetic test results in the context of local population databases, and
Improved healthcare delivery overall
Department of Endocrinology at SGH
The Department of Endocrinology at Singapore General Hospital manages patients with various lipid disorders. Individuals with suspected or confirmed FH can be referred to the department for diagnosis, risk stratification and optimisation of their lipid disorder.
Children’s Lipid Centre at KKH
The Children's Lipid Clinic at KK Women’s and Children’s Hospital welcomes referrals for children up to 18 years with suspected or confirmed FH. To reduce long-term cardiovascular risks, the multidisciplinary team prioritises early diagnosis and personalised management plans.
For more information or to make a referral, please contact 6294 4050. For urgent referrals, please call 6293 4044 to speak with an endocrinologist.
Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM, DePalma SM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;80(14):1366–418.
Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, et al. Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72(6):662–80.
Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects. J Am Coll Cardiol. 2020;75(20):2553–66.
McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB. Diagnosis and treatment of heterozygous familial hypercholesterolemia. J Am Heart Assoc. 2019;8(24):1–16.
MOH. ACE Clinical Guidelines on Lipid Management: Focus on cardiovascular risk. ACE Clin Guidel [Internet]. 2023;(December).
Clin Asst Prof Iswaree Devi BalakrishnanConsultant, SingHealth Duke-NUS Genomic Medicine Centre;Department of Cardiology, National Heart Centre Singapore;NHCS Cardiology @ SKH, Sengkang General Hospital
Clinical Assistant Professor Iswaree Devi Balakrishnan is a Consultant with the Department of Cardiology at the National Heart Centre Singapore. Her sub-specialty interests are in heart failure, cardiovascular genetics and echocardiography.
Clin Assoc Prof Eric LimSenior Consultant, Department of Cardiology, National Heart Centre Singapore
Clinical Associate Professor Eric Lim is a Senior Consultant with the Department of Cardiology at the National Heart Centre Singapore, with special expertise in electrophysiology and pacing.
Dr Tan Hong ChangDirector, Research, SingHealth Duke-NUS Diabetes Centre;Senior Consultant, Department of Endocrinology, Singapore General Hospital
Dr Tan Hong Chang is a Senior Consultant Endocrinologist at Singapore General Hospital. His clinical practice includes managing patients with various lipid disorders.
Clin Assoc Prof Tan Ee ShienHead & Director, Clinical Services, SingHealth Duke-NUS Genomic Medicine Centre;Head & Senior Consultant, Genetics Service, KK Women’s and Children’s Hospital;Senior Consultant, Department of Pathology and Laboratory Medicine;Children’s Lipid Centre, KK Women’s and Children’s Hospital
Clinical Associate Professor Tan Ee Shien leads the SingHealth-Duke NUS Genomic Medicine Centre (SDGMC) and the Genetics Service at KK Women’s and Children’s Hospital. She is the Deputy Chief Medical Officer for PRECISE and co-leads genomics research at SDGMC.
With expertise in paediatrics and genetic metabolic diseases, she champions access to quality care for genetic disorders. She directed Singapore’s national newborn screening programme from 2011 to 2023 and is committed to medical education and mentoring.
GPs can call the SingHealth Duke-NUS Genomic Medicine Centre for appointments at the following hotlines, visit the webpage for more information.
Singapore General Hospital: 6326 6060
KK Women’s and Children’s Hospital: 6692 2984
National Cancer Centre Singapore: 6324 8798
National Heart Centre Singapore: 6704 2222
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