What are the guidelines in Canada for genetic testing for hemochromatosis in an adult of European ancestry with a potential family history of the condition?

Genetic Testing Guidelines for Hemochromatosis in Canada

Adult individuals of European ancestry with a positive family history of first-degree relatives with hemochromatosis should undergo genetic testing for hemochromatosis after obtaining informed consent, according to the most recent international guidelines applicable to Canadian practice. 1

Primary Indication: Family History Screening

First-degree relatives (parents, siblings, children) of patients with confirmed hemochromatosis should receive both HFE genetic testing and simultaneous phenotypic screening (transferrin saturation and serum ferritin). 1 This dual approach is essential because:

• Genotype alone is neither necessary nor sufficient for diagnosis 1
• Penetrance in family members is significantly higher than in the general population 2
• Siblings show particularly high yield, with 33% demonstrating C282Y homozygosity 2

Genetic Testing Protocol for European Ancestry

Testing should focus on the C282Y mutation in the HFE gene, as this accounts for 85-90% of clinically affected patients of European origin. 1, 3 The testing panel should include:

• C282Y mutation (primary pathogenic variant) 1
• H63D mutation (can contribute to iron overload, particularly in compound heterozygotes) 1, 4

The C282Y variant is by far the most common genetic cause in individuals of European origin, with homozygosity (C282Y/C282Y) present in over 80% of patients with clinically overt hemochromatosis 1

Biochemical Screening Thresholds

Before or concurrent with genetic testing, obtain transferrin saturation and serum ferritin simultaneously—never rely on a single test. 4 Proceed with genetic testing if:

• Males: Transferrin saturation >50% and/or ferritin >300 μg/L 1
• Females: Transferrin saturation >45% and/or ferritin >200 μg/L 1
• Either sex: Persistently elevated transferrin saturation (≥45%) 1, 4

These thresholds indicate biochemical iron overload and warrant genetic confirmation 1, 4

Pre-Test Counseling Requirements

Obtain informed consent before genetic testing, discussing: 1, 4

• Available treatment (phlebotomy) and its efficacy
• Costs of testing and ongoing monitoring
• Implications for insurability and employment
• Psychological impact of disease labeling
• Family screening implications and cascade testing requirements
• Possibility of uncertain or variant genotypes

Clinical Scenarios Requiring Genetic Testing

Beyond family history, genetic testing is indicated for: 1

• Clinical and biochemical signs of hemochromatosis with elevated transferrin saturation and high serum ferritin
• Unexplained persistently elevated transferrin saturation
• Increased liver iron evident on liver biopsy or MRI (after biochemical assessment)
• Symptomatic patients with fatigue, arthralgias, hepatomegaly, diabetes, cardiomyopathy, or hypogonadism, even with borderline iron studies 4

Assessment for Advanced Disease After Positive Genetic Testing

If C282Y homozygosity is confirmed, assess for cirrhosis and end-organ damage. Liver biopsy is indicated if: 4

• Serum ferritin >1,000 μg/L
• Elevated liver enzymes (ALT or AST)
• Hepatomegaly on examination
• Age >40 years
• Platelet count <200

The combination of ferritin >1,000 μg/L with elevated liver enzymes and platelets <200 predicts cirrhosis in approximately 80% of C282Y homozygotes 4

Important Caveats and Pitfalls

Exclude secondary causes of hyperferritinemia before attributing elevated iron studies to hemochromatosis: 4

• Chronic alcohol consumption
• Inflammatory conditions
• Cell necrosis or malignancy
• Non-alcoholic fatty liver disease
• Metabolic syndrome

Serum ferritin can be falsely elevated due to inflammation, chronic liver disease, lymphomas, and other inflammatory conditions unrelated to iron overload 4, 2

Penetrance is variable: Only 50% of C282Y homozygotes develop end-organ damage in population-based studies, with higher penetrance in males and increasing with age 1, 5 This means genetic testing alone does not predict clinical disease severity.

Population Screening Not Recommended

Routine population-wide screening for hemochromatosis is not recommended due to low penetrance, uncertain benefit of early treatment in asymptomatic genotype-positive individuals, and potential for false positives 4, 2 Targeted case-finding based on family history, symptoms, or abnormal iron studies is the appropriate strategy.

Cascade Testing After Positive Diagnosis

When hemochromatosis is confirmed in the proband, recommend genetic testing for all first-degree relatives after appropriate counseling. 4, 2 For children of a proband, testing of the other parent is recommended to assess risk 2