Familial Hypercholesterolemia Testing | FH Genetic Test | Cytogenomix® Malaysia
Inherited Lipid Disorder

Familial Hypercholesterolemia Testing

Comprehensive genetic testing for Familial Hypercholesterolemia (FH). LDLR, APOB, and PCSK9 gene analysis for diagnosis of inherited high cholesterol and cascade screening.

1:250 HETEROZYGOUS FH
1:160,000 HOMOZYGOUS FH
90% LDLR MUTATIONS
10-14 DAYS TAT

Test Specifications

Technical details for Familial Hypercholesterolemia genetic testing

Test Code FH001 (LDLR/APOB/PCSK9 Panel), FH002 (Sequencing), FH003 (Comprehensive + MLPA)
Methodology Next-Generation Sequencing (NGS), Sanger confirmation, MLPA for large deletions/duplications
Genes Analyzed LDLR, APOB, PCSK9 (LDLRAP1 for recessive FH on request)
Mutations Detected Point mutations, small indels, large rearrangements (deletions/duplications) in LDLR gene
Sample Type 3-5 mL whole blood (EDTA purple top) | Saliva kit available
Turnaround Time 10-14 working days
Reporting Variant classification (pathogenic/likely pathogenic/VUS), cascade screening recommendations
Genetic Counseling Pre- and post-test counseling included

Understanding Familial Hypercholesterolemia

Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism characterized by severely elevated LDL cholesterol from birth, leading to premature atherosclerotic cardiovascular disease. It is one of the most common autosomal dominant disorders.

Key Facts:

  • Inheritance: Autosomal dominant (co-dominant for LDLR)
  • Prevalence: 1 in 250 individuals (heterozygous FH)
  • Genes: LDLR (90%), APOB (5-10%), PCSK9 (<1%)
  • Risk: 20x increased risk of coronary artery disease if untreated

FH is significantly underdiagnosed in Malaysia. Cascade screening of family members after identifying a proband is essential for prevention.

Familial Hypercholesterolemia Inheritance

Genes Associated with FH

Three main genes account for the majority of FH cases

LDLR

~90% of cases
  • LDL receptor protein
  • Chromosome 19p13.2
  • 18 exons
  • >2,500 mutations identified
  • Large deletions in 5-10%

APOB

5-10% of cases
  • Apolipoprotein B-100
  • Chromosome 2p24.1
  • 29 exons
  • Mostly missense mutations
  • R3500Q most common

PCSK9

<1% of cases
  • Proprotein convertase
  • Chromosome 1p32.3
  • 12 exons
  • Gain-of-function mutations
  • Drug target for PCSK9 inhibitors

Dutch Lipid Clinic Network Criteria

Clinical diagnostic criteria for FH (DLCN score)

Criteria Points
Family History
First-degree relative with premature CAD or vascular disease 1
First-degree relative with LDL >95th percentile 1
First-degree relative with tendon xanthomas or arcus cornealis 2
Children <18 years with LDL >95th percentile 2
Clinical History
Patient with premature CAD (men <55, women <60) 2
Patient with premature cerebral/peripheral vascular disease 1
Physical Examination
Tendon xanthomas 6
Arcus cornealis before age 45 4
LDL-Cholesterol Level
>8.5 mmol/L (>325 mg/dL) 8
6.5-8.4 mmol/L (251-325 mg/dL) 5
5.0-6.4 mmol/L (191-250 mg/dL) 3
4.0-4.9 mmol/L (155-190 mg/dL) 1
DNA Analysis
Functional mutation in LDLR, APOB, or PCSK9 8
Definite FH: >8 points
Probable FH: 6-8 points
Possible FH: 3-5 points

LDL Cholesterol Levels by Age and Genotype

Typical untreated LDL-C levels in FH

Normal
<3.0
mmol/L
Children (heterozygous)
4.0-7.0
mmol/L
Adults (heterozygous)
5.0-13.0
mmol/L
Homozygous FH
>13.0
mmol/L

Note: LDL levels vary by specific mutation and genetic modifiers. Genetic testing provides definitive diagnosis.

Clinical Features of FH

Physical signs and complications

Tendon Xanthomas

  • Cholesterol deposits in tendons
  • Most common in Achilles tendon
  • Also in extensor hand tendons
  • Pathognomonic for FH

Corneal Arcus

  • White/gray ring around cornea
  • Before age 45 is significant
  • Due to lipid deposition

Premature CAD

  • Men <55 years, Women <60 years
  • Myocardial infarction
  • Coronary revascularization
  • Sudden cardiac death

Xanthelasma

  • Cholesterol deposits in eyelids
  • Yellowish plaques
  • Not specific to FH

FH Prevalence and Risk

Global and Malaysian perspective

1:250
Heterozygous FH
1:160,000
Homozygous FH
20x
Increased CAD Risk
<10%
Diagnosed in Malaysia

Autosomal Dominant Inheritance

Understanding the risk for family members

One Affected Parent

Affected
Normal
Affected
Normal
Affected
Normal
50% risk for each child

No skipped generations

Both Parents Affected

Affected
Affected
Heterozygous
Heterozygous
Heterozygous
Homozygous
25% risk homozygous FH

Severe, often childhood CAD

Cascade Screening: When a pathogenic variant is identified, first-degree relatives have a 50% chance of carrying the same variant and should be tested.

Treatment and Management

Lifelong management of FH

Lifestyle

  • Heart-healthy diet (low saturated fat)
  • Regular exercise
  • No smoking
  • Healthy weight maintenance

Pharmacotherapy

  • High-intensity statins (atorvastatin, rosuvastatin)
  • Ezetimibe (cholesterol absorption inhibitor)
  • PCSK9 inhibitors (evolocumab, alirocumab)
  • Bile acid sequestrants

Homozygous FH

  • Lipoprotein apheresis
  • Lomitapide (MTP inhibitor)
  • Evinacumab (ANGPTL3 inhibitor)
  • Liver transplantation (curative)

Reproductive Options

  • Cascade screening of family
  • Prenatal diagnosis (rarely indicated)
  • PGT for homozygous FH families

Cascade Screening

The key to preventing premature CAD in families

Index Case (Proband)
First-Degree Relatives
Second-Degree Relatives
Early Treatment
Benefits of Cascade Screening
  • Identifies affected relatives before events
  • Enables early statin therapy
  • Reduces CAD mortality by >50%
  • Cost-effective prevention strategy
Expected Yield
  • Each proband → ~3-5 affected relatives
  • 50% of first-degree relatives positive
  • 25% of second-degree relatives positive

Who Should Be Tested?

Indications for FH genetic testing

Elevated LDL Cholesterol

Adults with LDL >4.9 mmol/L, children with LDL >4.0 mmol/L despite lifestyle measures

Physical Signs

Tendon xanthomas, corneal arcus before age 45, xanthelasma with high LDL

Premature CAD

Men <55 years, women <60 years with myocardial infarction or coronary intervention

Family History

First-degree relatives of known FH patients (cascade screening)

Frequently Asked Questions

Common questions about FH testing

What is the difference between heterozygous and homozygous FH?

Heterozygous FH (HeFH) is caused by one mutated gene copy, with LDL typically 4-13 mmol/L. Homozygous FH (HoFH) has two mutated copies, with LDL often >13 mmol/L and presents in childhood with severe CAD risk.

Can FH be treated?

Yes, but it requires lifelong treatment. High-intensity statins are first-line, often combined with ezetimibe. PCSK9 inhibitors are highly effective. With treatment, life expectancy approaches normal.

What is the risk if FH is untreated?

Men with untreated FH have a 50% risk of myocardial infarction by age 50; women have a 30% risk by age 60. Early treatment dramatically reduces this risk.

Why is genetic testing needed if clinical criteria exist?

Genetic testing provides definitive diagnosis, guides cascade screening, identifies those needing aggressive treatment, and distinguishes FH from polygenic hypercholesterolemia.

What is a VUS in FH testing?

A Variant of Uncertain Significance means the genetic change's impact on LDLR function is unknown. These require family segregation studies and are not used for cascade screening.

How often should children be tested if a parent has FH?

Children of affected parents should be tested by age 5-10 (or earlier if concerns). Genetic testing can be done at any age; lipid testing from age 2.

Ready to Order FH Testing?

Our genetic counselors and cardiology specialists are ready to assist with test selection, cascade screening, and result interpretation.

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