In Canada, how is hereditary hypercholesterolemia diagnosed?

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Last updated: March 13, 2026 • View editorial policy

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Diagnosis of Familial Hypercholesterolemia in Canada

In Canada, diagnose familial hypercholesterolemia (FH) using the Simplified Canadian Definition, which combines clinical criteria (severe hypercholesterolemia with specific LDL-C thresholds, family history, and physical signs) with optional genetic testing to confirm probable cases and enable cascade screening. 1

Initial Diagnostic Approach

Step 1: Lipid Screening and Secondary Cause Exclusion

  • Obtain a fasting or nonfasting lipid profile with LDL-C calculated using the Friedewald formula 1
  • If the patient is already on statins with or without ezetimibe, impute the baseline LDL-C (pre-treatment value) and use this for diagnostic criteria 1
  • Rule out secondary causes of elevated LDL-C before diagnosing FH: severe or untreated hypothyroidism, nephrotic syndrome, hepatic disease (biliary cirrhosis), and medications especially antiretroviral agents 1

Step 2: Apply the Canadian Clinical Diagnostic Criteria

The Simplified Canadian Definition (most commonly used across 5 of 8 provinces) classifies FH as follows 2:

Definite FH requires:

  • A first-degree relative with elevated LDL-C AND
  • Either severe hypercholesterolemia OR a causal DNA mutation in LDLR, APOB, or PCSK9 genes 1

Probable FH requires:

  • Severe hypercholesterolemia (specific LDL-C thresholds based on age and treatment status) OR
  • Clinical signs of FH (xanthomas or family history of premature cardiovascular disease) 1

Severe Hypercholesterolemia is defined by:

  • Untreated LDL-C levels that meet age-specific thresholds indicating genetic hypercholesterolemia 1

Genetic Testing Strategy

When to Order Genetic Testing

  • Request genetic testing to confirm diagnosis in "probable" cases 1
  • Genetic testing identifies pathogenic variants in 30%-80% of individuals with clinical FH 1
  • Testing is particularly valuable because patients with LDL-C >5 mmol/L and an FH-causing variant have a 22-fold excess risk for atherosclerotic cardiovascular disease (ASCVD), compared to only 6-fold risk in those without a variant 1

Genetic Testing Panel

  • Test for variants in LDLR (86.4% of cases), APOB (14.2%), and PCSK9 genes 3
  • Most pathogenic variants are in the LDLR gene, with 1%-5% in APOB and up to 3% in PCSK9 1
  • Include multiplex ligation-dependent probe amplification (MLPA) of LDLR to detect large deletions/duplications 3
  • The Quebec MSSS partial panel (11 common French-Canadian variants) only accounts for 48% of variants identified by full next-generation sequencing, so full NGS panels are superior 3

Important Caveats About Genetic Testing

Clinical FH genetic testing availability varies significantly by province 2:

  • Available in 7 of 8 provinces surveyed (British Columbia being the exception) 2
  • Eligibility criteria and utilization differ substantially across provinces 2
  • Most genetic counseling programs receive ≤3 referrals per site per month, except Quebec which reports higher rates 2

Reasons for negative genetic testing despite clinical FH include 1:

  • Genetic variant of uncertain significance
  • Polygenic cause (multiple allelic variations assessed by "polygenic risk score")
  • Variants not detected by current sequencing (complex rearrangements, noncoding variants)
  • Rare gene variants (STAP1, LDLRAP1, APOE, LIPA)
  • Unidentified causative genes

Cascade Screening

Once FH is diagnosed, perform cascade screening of first-degree relatives 1:

  • Lipid screening of all first-degree relatives is recommended 1
  • Consider genetic testing in relatives if a pathogenic variant was identified in the proband 1
  • This approach has proven effective in the Netherlands for identifying and treating new cases 1
  • Genetic testing facilitates cascade screening and increases lipid-lowering therapy use 1

Opportunistic Screening

Screen young individuals presenting with acute coronary syndrome for FH, as this has proven effective for diagnosis 1

Clinical Impact of Genetic Confirmation

  • Genetic testing reclassified 39.3% of patients from probable FH to definite FH in a Quebec cohort 3
  • Positive genetic test results are associated with increased use of lipid-lowering therapy and improved lipid control 1
  • Carriers of pathogenic LDLR variants have a 10-fold higher risk of premature ASCVD compared to the general population 1
  • The presence of clinical signs plus a pathogenic variant increases ASCVD risk by 11.6-fold, compared to 4.6-fold with clinical signs alone 1

References

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