Educational

Screening and Genetic Testing

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by

Saim Khalid
in

Introduction

Familial hypercholesterolemia (FH) is one of the most common inherited metabolic disorders, characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C) and a markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Despite its high prevalence—affecting approximately 1 in 200–250 individuals globally—FH remains grossly underdiagnosed and undertreated.

Timely identification of FH is critical. Individuals with FH who remain untreated are at up to 20-fold higher risk of early-onset coronary artery disease (CAD) compared with the general population. Early screening and treatment can normalize life expectancy, particularly when statins and other lipid-lowering therapies are initiated during childhood or early adulthood.

This makes screening and genetic testing the cornerstone of FH management. Screening allows clinicians to detect at-risk individuals early, while genetic testing confirms diagnosis, enables cascade screening of relatives, and informs therapeutic decisions.

This article explores in detail:

  • The rationale for FH screening.
  • Available diagnostic criteria.
  • Genetic testing strategies.
  • Cascade screening and its public health significance.
  • Ethical and practical challenges.
  • Future directions in precision medicine.

Section 1: Why Screening for FH Matters

1.1 The Burden of Disease

  • FH is highly prevalent, but <10–20% of affected individuals are formally diagnosed worldwide.
  • Undiagnosed FH leads to missed opportunities for prevention, with many patients first presenting with myocardial infarction in early adulthood.
  • Studies show that early statin initiation in FH children dramatically reduces ASCVD risk and aligns outcomes with non-FH individuals.

1.2 Rationale for Screening

  • FH is present from birth; cholesterol accumulation is lifelong.
  • LDL-C testing in childhood is inexpensive and can identify at-risk individuals before symptoms occur.
  • Early detection prevents sudden cardiac death, premature strokes, and costly interventions such as coronary bypass or heart transplantation.

Section 2: Clinical Diagnosis Before Genetic Testing

Before genetic confirmation, FH can be suspected based on lipid profile, physical signs, and family history.

2.1 Clinical Diagnostic Criteria

Several international guidelines use standardized scoring systems:

  1. Dutch Lipid Clinic Network (DLCN) Criteria
    • Assigns points for LDL-C levels, family history of premature CAD, physical findings (xanthomas, arcus cornealis), and DNA mutation.
    • Diagnosis: Definite FH (score ≥8), Probable FH (6–7), Possible FH (3–5).
  2. Simon Broome Criteria (UK)
    • Based on total cholesterol or LDL-C thresholds, family history, and physical stigmata.
    • Classification: Definite FH (with tendon xanthomas or genetic mutation) or Possible FH.
  3. Make Early Diagnosis to Prevent Early Death (MEDPED) Criteria (US)
    • Age-specific LDL-C cutoffs for FH diagnosis, considering family history.

2.2 Limitations of Clinical Diagnosis

  • LDL-C levels overlap between FH and polygenic/environmental hypercholesterolemia.
  • Physical signs (xanthomas, arcus cornealis) are absent in many heterozygous FH patients.
  • Genetic testing provides definitive confirmation.

Section 3: Genetic Basis of FH

FH is predominantly caused by mutations in three genes:

  1. LDLR (Low-Density Lipoprotein Receptor gene) – ~60–80% of cases.
  2. APOB (Apolipoprotein B gene) – 5–10% of cases.
  3. PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9 gene) – <1% of cases.

Rarely, mutations in LDLRAP1 cause autosomal recessive FH.

These mutations impair LDL clearance, leading to elevated plasma LDL-C. Identifying the causative gene helps in prognosis and therapy (e.g., PCSK9 mutation carriers may particularly benefit from PCSK9 inhibitors).

Section 4: Genetic Testing for FH

4.1 When to Consider Genetic Testing

  • LDL-C ≥190 mg/dL (≥4.9 mmol/L) in adults or ≥160 mg/dL in children.
  • Presence of tendon xanthomas or arcus cornealis before age 45.
  • Premature ASCVD in the patient or family (men <55, women <65).
  • First-degree relative with FH or elevated LDL-C.

4.2 Genetic Testing Methods

  1. Targeted Mutation Analysis
    • Screens for common known mutations (e.g., APOB p.Arg3500Gln).
    • Cost-effective but limited in scope.
  2. Sanger Sequencing
    • Used for LDLR, APOB, and PCSK9 genes.
    • Gold standard but time-consuming and costly for large genes.
  3. Next-Generation Sequencing (NGS)
    • Enables high-throughput analysis of multiple genes simultaneously.
    • Detects rare and novel mutations.
    • Now widely used in FH testing panels.
  4. Multiplex Ligation-dependent Probe Amplification (MLPA)
    • Detects large deletions or duplications in LDLR not found by sequencing.

4.3 Yield of Genetic Testing

  • Mutation detection rates vary:
    • 60–80% in clinically definite FH.
    • 20–40% in possible FH.
  • Some patients with FH phenotype have polygenic hypercholesterolemia, explained by accumulation of common LDL-raising variants.

Section 5: Cascade Screening – A Public Health Imperative

5.1 What is Cascade Screening?

Cascade screening involves testing biological relatives of an index case (proband) with FH.

Process:

  1. Identify a patient with FH (index case).
  2. Offer lipid profile and/or genetic testing to first-degree relatives.
  3. Extend testing to second- and third-degree relatives if positive.

5.2 Why Cascade Screening Works

  • Cost-effective compared to population-wide screening.
  • Identifies multiple cases from a single index patient.
  • Early detection reduces ASCVD events and healthcare burden.

5.3 Models of Cascade Screening

  1. Lipid-based cascade screening: Relatives screened with LDL-C measurements.
  2. Genetic cascade screening: Relatives tested for the familial mutation.

5.4 International Success Stories

  • Netherlands: One of the most successful FH cascade screening programs, identifying >70% of FH cases.
  • UK, Spain, Norway: National programs combining lipid and genetic testing.
  • US and many Asian countries: Programs are less developed but growing.

Section 6: Universal and Opportunistic Screening

6.1 Universal Pediatric Screening

  • Recommended by the US National Heart, Lung, and Blood Institute (NHLBI).
  • All children screened for cholesterol between ages 9–11 and again at 17–21.
  • Detects FH before cardiovascular damage begins.

6.2 Opportunistic Screening

  • Testing LDL-C in adults during routine care, particularly if LDL-C ≥190 mg/dL.
  • Less systematic but captures at-risk individuals.

6.3 Comparison

  • Universal pediatric screening ensures early capture but requires broad healthcare infrastructure.
  • Cascade screening remains the most cost-effective model.

Section 7: Benefits of Genetic Testing

  1. Diagnostic Certainty
    • Confirms FH even in borderline LDL-C cases.
    • Differentiates monogenic FH from polygenic hypercholesterolemia.
  2. Cascade Screening
    • Allows precise identification of affected relatives carrying the mutation.
  3. Therapeutic Guidance
    • PCSK9 mutations highlight the potential benefit of PCSK9 inhibitors.
    • Severe LDLR-null mutations may require more aggressive therapy.
  4. Psychological Impact
    • Provides clarity and motivation for lifestyle adherence.

Section 8: Challenges in Screening and Testing

8.1 Underdiagnosis and Lack of Awareness

  • Many physicians under-recognize FH.
  • Patients may not be referred for genetic testing.

8.2 Access and Cost

  • Genetic testing may be unavailable or unaffordable in many countries.
  • Insurance coverage varies widely.

8.3 Variants of Uncertain Significance (VUS)

  • Genetic sequencing may reveal novel variants whose pathogenicity is unclear.
  • Creates challenges in counseling and decision-making.

8.4 Ethical Considerations

  • Informed consent, especially in pediatric testing.
  • Psychological burden of genetic risk.
  • Confidentiality and potential discrimination (e.g., insurance, employment).

Section 9: Integration into Clinical Practice

9.1 Multidisciplinary FH Clinics

  • Teams including cardiologists, geneticists, lipidologists, and counselors.
  • Provide genetic testing, cascade screening, and long-term follow-up.

9.2 Role of Primary Care

  • Initial suspicion based on LDL-C.
  • Referral for genetic testing and specialist care.

9.3 Digital Health Tools

  • Registries, electronic alerts, and family-tracing apps can enhance cascade screening.

Section 10: Future Directions

10.1 Precision Medicine

  • Polygenic risk scores (PRS) to distinguish FH from polygenic hypercholesterolemia.
  • Gene editing (CRISPR-Cas9) targeting LDLR, APOB, or PCSK9 mutations.

10.2 Expanded Genetic Panels

  • Inclusion of emerging genes linked to FH-like phenotypes.

10.3 Global Public Health Strategies

  • Establishing national FH registries.
  • Mandatory reporting and cascade screening frameworks.
  • Integration with universal cholesterol screening.

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