American College of Medical Genetics and Genomics

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Released July 10, 2015; sources updated Updated July 1, 2021

Don’t order HFE genetic testing for a patient without iron overload or a family history of HFE-associated hereditary hemochromatosis.

The majority of hereditary hemochromatosis is due to inheritance of HFE gene mutations. HFE gene mutations are common among individuals of European ancestry; however, only a small proportion of individuals with these mutations develop clinical disease. Other genetic and non-genetic factors contribute to disease expression. HFE genotyping should only be performed among individuals with iron overload (e.g., elevated fasting transferrin saturation >45%) or a known family history of HFE-associated hereditary hemochromatosis. In the setting of genome or exome sequencing, it is now recommended that patients who are homozygous for the pathogenic variant C282Y in HFE should receive this result and consider evaluation.


The items on the ACMG list are provided solely for informational purposes and are not intended as a substitute for consultation with a medical professional. In determining the propriety of any specific procedure or test, patients should consult with their individual providers and providers should apply their own professional judgment to the specific clinical circumstances presented by each individual patient.

How The List Was Created

The American College of Medical Genetics and Genomics (ACMG) list relies on input from a number of committees in developing clinical practice guidelines and laboratory technical standards and guidelines. For the Choosing Wisely® campaign, input from the Laboratory Quality Assurance Committee, Professional Practice and Guidelines Committee and Therapeutics Committee was solicited. A list of 18 items was reviewed by the ACMG Board of Directors and the five items currently thought to most likely improve quality and reduce waste related to genetic testing were selected. The recommended list was approved by the ACMG Board of Directors, March 24, 2015.

For the ACMG’s disclosure and conflict of interest policy, please visit www.acmg.net.

Sources

Porto G, Brissot P, Swinkels DW, Zoller H, Kamarainen O, Patton S, Alonso I, Morris M, Keeney S. EMQN best practice guidelines for molecular genetic diagnosis of hereditary hemochromatosis (HH). European Journal of Human Genetics. 2016;24:479-495.

Hanson EH, Imperatore G, Burke W. HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. Am J Epidemiol. 2001 Aug 1;154(3):193-206.

King C, Barton DE. Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related) hereditary haemochromatosis. BMC Med Genet. 2006 Nov 29;7:81.

Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS; American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011 Jul;54(1):328-43.

European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010 Jul;53(1):3-22.

Miller DT, Lee K, Chung WK, et al. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College
of Medical Genetics and Genomics (ACMG). Genet Med. 2021. https://doi.org/10.1038/s41436-021-01172-3

Miller DT, Lee K, Gordon AS, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the
American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021. https://doi.org/10.1038/s41436-021-01171-4