What are the downsides of ordering genetic testing for hereditary hemochromatosis (HH) without clear evidence of iron overload?

From the Guidelines

Ordering genetic testing for iron overload without clear evidence is generally not recommended due to several significant downsides. Premature genetic testing can lead to unnecessary anxiety and medical interventions if variants of uncertain significance are detected, as these results often require clinical interpretation that may be challenging without supporting clinical or laboratory evidence of iron overload. The testing is expensive and may not be covered by insurance without documented clinical necessity, creating financial burden for patients. False positive results can occur, potentially leading to unnecessary monitoring or treatments with their own risks and side effects. Additionally, genetic testing results may have implications for family members and could create psychological distress or concerns about genetic discrimination, despite legal protections in place. Genetic test results also require proper interpretation by healthcare providers with expertise in genetics, and without clear clinical indications, the results may be difficult to contextualize appropriately. A more prudent approach involves first conducting standard iron studies (serum ferritin, transferrin saturation) to establish evidence of iron overload before proceeding to genetic testing for conditions like hereditary hemochromatosis, as recommended by the USPSTF 1 and other clinical practice guidelines 1. This approach is supported by the latest guidelines on the molecular diagnosis of haemochromatosis, which suggest that the management of patients with p.C282Y/p.H63D compound heterozygosity or p.H63D homozygosity should be guided by their phenotypic presentation and the presence of additional risk factors, not the genotype alone 1. Some key points to consider when evaluating the need for genetic testing include:

• The potential for unnecessary anxiety and medical interventions
• The expense of genetic testing and potential lack of insurance coverage
• The risk of false positive results and unnecessary monitoring or treatment
• The need for proper interpretation of genetic test results by healthcare providers with expertise in genetics
• The importance of establishing evidence of iron overload through standard iron studies before proceeding to genetic testing. It is essential to weigh these factors and consider the latest clinical practice guidelines when deciding whether to order genetic testing for iron overload.

From the Research

Downsides of Ordering Genetic Testing without Clear Evidence of Iron Overload

• The studies provided do not directly address the downsides of ordering genetic testing without clear evidence of iron overload 2, 3, 4, 5, 6.
• However, it can be inferred that unnecessary genetic testing may lead to unnecessary costs, anxiety, and potential misdiagnosis or misinterpretation of results.
• Additionally, genetic testing for iron overload disorders, such as hereditary hemochromatosis, should be pursued in evaluation of hyperferritinemia, and a secondary cause for iron overload should be considered if HFE genetic testing is negative for the C282Y homozygous or C282Y/H63D compound heterozygous mutations 4.
• The decision to order genetic testing should be based on a thorough medical evaluation and clear evidence of iron overload, rather than relying solely on genetic testing results.
• It is essential to consider the potential risks and benefits of genetic testing and to discuss the results with a healthcare professional to ensure accurate interpretation and appropriate management 5, 6.