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FOR THE TESTED INDIVIDUAL – This information is intended to assist your physician or other qualified health care professional as part of their comprehensive assessment of the best approach to managing your genetic test results. It is not specific advice for your care and it does not replace consultation with a qualified health care professional. You should not alter your medical care based on this report without speaking to, and receiving guidance from, your physician based on your specific case.
FOR THE CLINICIAN – This information was prepared on the date indicated on the file and may have been updated subsequently. Please check UpToDate (UpToDate.com) for the latest version of this and other gene test interpretation monographs. UpToDate subscribers can access these monographs by entering the gene name or the phrase "Gene test interpretation" into the UpToDate search box. Your use of this information is subject to the terms set forth at https://www.uptodate.com/legal/license and any other terms in any applicable license agreement. This information is no substitute for individual patient assessment based on the healthcare provider's evaluation of each patient that includes personal and family history, findings from the physical examination, laboratory and other testing, and other factors unique to the patient. The information should be used as a tool to help the clinician reach diagnostic and treatment decisions, bearing in mind that individual and unique circumstances may lead to decisions other than those presented. The opinions expressed are those of the monograph's authors and editors.
Supported by an unrestricted educational grant from AncestryHealth®.
- Clara Camaschella, MD
- Meadow Heiman, MS, LCGC, CCRC
- Section Editor:
- Robert T Means, Jr, MD, MACP
- Deputy Editor:
- Jennifer S Tirnauer, MD
INTRODUCTION — This monograph summarizes the interpretation of genetic testing for HFE, the main gene associated with hereditary iron overload. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the care of the tested person. These subjects are discussed separately . (See 'UpToDate topics' below.)
How to read the report — The checklist provides important caveats for genetic testing (table 1). Any result obtained for research or by direct-to-consumer testing that has clinical implications for the tested individual or their relatives should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory with verified patient identification.
Two variants in HFE are associated with most cases of hereditary hemochromatosis (HH). Both are point mutations. Testing for C282Y, the most common variant, is standard; many laboratories test for H63D.
●C282Y – Substitution of tyrosine (Y) for cysteine (C) at amino acid 282 (also written p.Cys282Tyr) . In the DNA, guanine (G) is replaced by adenine (A) at nucleotide 845 (written c.G845A or c.845G>A).
●H63D – Substitution of aspartic acid (D) for histidine (H) at amino acid 63 (also written p.His63Asp). In the DNA, cytosine (C) is replaced by G at nucleotide 187 (written c.C187G or c.187C>G).
Some laboratories report the HFE S65C mutation, but most experts do not consider S65C to confer an increased risk of iron overload (it is considered a benign variant).
Some cases of iron overload are associated with rare variants such as HFE gene deletions or variants affecting other iron regulatory genes (table 2). Testing for these may be indicated in suspected or known juvenile hemochromatosis. (See "HFE and other hemochromatosis genes", section on 'Rare HFE variants' and "HFE and other hemochromatosis genes", section on 'Non-HFE hemochromatosis'.)
Iron overload — The diagnosis of iron overload is made using iron studies and other evaluations to quantify organ iron deposition. Genetic testing is an adjunct that provides additional information about the cause and facilitates identification of potentially affected family members, but genetic testing alone cannot determine if an individual has iron overload or requires treatment.
Conversely, individuals with iron overload should receive appropriate treatment regardless of genetic test results, and first-degree relatives of an individual with iron overload not due to transfusions generally should be screened with iron studies regardless of their genetic test results. (See 'Further evaluation and management' below.)
HFE-related hemochromatosis is an autosomal recessive disorder with low penetrance (genetics terms are defined in the glossary (table 3)). A pathogenic (disease-causing) variant affecting both HFE alleles (one inherited from each parent) is generally required for iron overload to develop (table 4). However, the majority of individuals with biallelic HFE variants will not develop iron overload.
●Homozygosity for the C282Y variant (C282Y/C282Y) accounts for 80 to 100 percent of hemochromatosis cases; compound heterozygosity with H63D (C282Y/H63D) accounts for many of the remainder.
•The likelihood of iron overload in C282Y/C282Y homozygotes has been cited at 1 percent in women to 28 percent in men . The majority of C282Y homozygotes will not develop iron overload. However, most of these individuals will have abnormal iron studies (increased iron, transferrin saturation [TSAT], and ferritin). Development of iron overload is age-related (in women, generally after menopause; in men, generally after age 40). (See "HFE and other hemochromatosis genes", section on 'Likelihood of developing iron overload'.)
•C282Y/H63D confers an even lower risk of iron overload than C282Y/C282Y. Iron overload is typically mild and develops only in the presence of other risk factors.
•Less common forms of hemochromatosis with higher penetrance and a younger age of onset may be caused by variants in other iron regulatory genes (table 2). (See "HFE and other hemochromatosis genes", section on 'Non-HFE hemochromatosis'.)
•Iron overload may also be caused or exacerbated by other risk factors including liver disease (alcoholic or other), thalassemia or other disorder of ineffective erythropoiesis, or blood transfusions (typically more than 10 to 20 units of red blood cells [RBCs]). (See "Approach to the patient with suspected iron overload", section on 'Causes of iron overload'.)
●Homozygosity for H63D (H63D/H63D) generally does not confer an increased risk of iron overload unless other risk factors are present.
●Heterozygosity (C282Y/wild-type or H63D/wild-type) is not associated with an increased risk of iron overload relative to the general population.
Organ damage — For those with iron overload, the magnitude of iron burden may progress over time. Other factors can influence the rate of iron accumulation. As examples, iron burden is reduced by regular menstrual periods and pregnancy; iron uptake is accelerated by liver disease or consumption of excess alcohol (generally, >10 drinks per week in women or >15 drinks per week in men).
Organ injury is generally of greatest concern as the total body iron burden increases over decades. However, organ injury can occur with lower levels of excess iron. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Clinical manifestations'.)
The following may be seen:
●Other endocrinopathies including hypopituitarism, hypogonadism, and hypothyroidism
●Skin pigmentation (bronze skin)
●Increased susceptibility to infection
If untreated, severe or even fatal complications such as cirrhosis, hepatocellular cancer, heart failure, or arrhythmias may develop. Removal of iron with regular phlebotomy can prevent (and in some cases reverse) these complications. (See 'Further evaluation and management' below.)
FURTHER EVALUATION AND MANAGEMENT
People not previously diagnosed with iron overload — Iron studies (serum iron, ferritin, transferrin or total iron binding capacity [TIBC], and transferrin saturation [TSAT]) are the first step for determining whether iron overload is present.
●We obtain iron studies for individuals with homozygosity for HFE C282Y (C282Y/C282Y) or compound heterozygosity with H63D (C282Y/H63D) (algorithm 1).
●For individuals with negative testing for HFE C282Y or with another genotype such as homozygosity for H63D or heterozygosity for C282Y, H63D, or S65C, we only obtain iron studies if there are other reasons to do so, such as a family history of hereditary hemochromatosis (HH) or unexplained liver disease, heart failure, endocrine disorders, or arthropathy (algorithm 1). (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Genotype-phenotype correlations' and "Management and prognosis of hereditary hemochromatosis", section on 'Heterozygotes'.)
For children and adolescents, testing may be deferred until adulthood unless there is a positive family history of early-onset iron overload or another cause of iron overload such as multiple transfusions or thalassemia. (See 'Iron overload' above.)
Typically, individuals being evaluated for iron overload also have a complete blood count (CBC) and liver function tests. Discussion of alcohol intake and other causes of liver disease may be indicated.
Increased iron stores are indicated by a high serum ferritin (>300 ng/mL in men or postmenopausal women; >200 ng/mL in premenopausal women) and high TSAT (>45 percent in men; >55 percent in women); the thresholds vary in different guidelines [4-6]. Increased hepatic transaminases may be seen but are nonspecific.
Subsequent testing is individualized (algorithm 1):
●Repeat iron studies (annually or less frequently) may be reasonable for younger individuals (premenopausal women or men <40 years) or those with normal or borderline values who remain at risk based on family history of genotype.
●Liver and/or cardiac magnetic resonance imaging (MRI) is often appropriate for those with a ferritin >1000 ng/mL.
●Liver biopsy is generally used when other diagnoses are being considered that require histologic evaluation.
This testing may be performed by the individual's primary clinician or by a specialist such as a hematologist, hepatologist, or genetics expert. (See 'Locating a genetics expert' below.)
The rationale for testing and interpretation of the results are discussed separately. (See "Approach to the patient with suspected iron overload", section on 'Sequence and interpretation of testing' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Diagnostic evaluation'.)
People known to have iron overload — Individuals with known iron overload require treatment regardless of their HFE genotype. The goal is to prevent organ injury or reverse it if possible.
Phlebotomy is the mainstay of treatment. Regular phlebotomies over time can completely deplete the excess iron and can prevent, or in some cases reverse, organ damage and other complications. The indications for phlebotomy, timing of initiation, pace, and number of phlebotomies depend on the degree of iron excess. Following removal of excess iron, maintenance phlebotomies are generally continued throughout adulthood. (See "Management and prognosis of hereditary hemochromatosis", section on 'Phlebotomy'.)
HFE testing may be helpful in identifying a genetic contribution to iron overload, with the following potential implications for those who test positive:
●Lifelong need to monitor iron burden and to perform phlebotomies when indicated
●Testing of at-risk relatives
●Motivation to avoid excess alcohol or other hepatotoxins
Phlebotomy and monitoring is often done by a hematologist, but the primary clinician can also manage therapy if they have the appropriate expertise and resources. Details of the procedure and other subjects such as dietary modifications and blood donation by people with hemochromatosis are discussed separately. (See "Management and prognosis of hereditary hemochromatosis".)
For those with documented HFE mutations, their first-degree relatives should be informed and in many cases tested, either by the relative's primary clinician or a genetics expert. (See 'At-risk relatives' below and 'Locating a genetics expert' below.)
For individuals with unexplained iron overload (not due to thalassemia or transfusions) who test negative for HFE mutations or who are found to be heterozygous for an HFE mutation, it may be appropriate to refer to a genetics expert for more advanced testing of other HFE and/or non-HFE variants. This is especially useful in rare cases of hemochromatosis in a child, adolescent, or young adult. (See "HFE and other hemochromatosis genes", section on 'Juvenile hemochromatosis'.)
At-risk relatives — First-degree relatives of an individual with HFE C282Y are at risk for inheriting the variant. This includes relatives of a tested individual who is C282Y/C282Y homozygous, C282Y/H63D compound heterozygous, or C282Y heterozygous.
●First-degree relatives of a heterozygote have a 50 percent chance of carrying (or inheriting) the variant. Because the frequency of C282Y is relatively high in certain populations, it is also possible for the other parent to carry the variant and for some of these relatives to be homozygous or compound heterozygous .
●Offspring of a C282Y homozygote or compound heterozygote (C282Y/H63D) will inherit at least one of the variants. Full siblings of a homozygote or compound heterozygote have a 25 percent chance (or higher, depending on the genotype of both parents) of themselves also being a homozygote or compound heterozygote.
Based on these probabilities, genetic testing of any first-degree relative is reasonable if the tested individual carries the C282Y variant. Testing may be omitted or deferred if the results would not alter management, such as for older individuals or those with acute medical problems. If indicated, testing should generally be deferred until the tested individual's results have been reviewed and caveats are addressed, and until the relative is 18 or older, to allow for proper informed consent. (See 'How to read the report' above and "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)
At-risk relatives of an individual with documented iron overload not explained by an acquired condition should generally have iron studies testing, regardless of the tested individual's genotype. (See "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)
Discussions of risk and initial testing can be performed by the relative's primary clinician. If the relative requires counseling, additional information, or testing that cannot be provided by the primary clinician, referral to a genetics expert is reasonable. (See 'Resources' below.)
●Genetics – (See "HFE and other hemochromatosis genes".)
●Diagnosis of hereditary hemochromatosis (HH) – (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
●Treatment of HH – (See "Management and prognosis of hereditary hemochromatosis".)
●Overview of iron overload – (See "Approach to the patient with suspected iron overload".)
Locating a genetics expert
●Genetic counselor – The National Society of Genetic Counselors (NSGC)
●Clinical geneticist – The American College of Medical Genetics and Genomics (ACMG)
- Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
- Cullen LM, Gao X, Easteal S, Jazwinska EC. The hemochromatosis 845 G-->A and 187 C-->G mutations: prevalence in non-Caucasian populations. Am J Hum Genet 1998; 62:1403.
- Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008; 358:221.
- European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010; 53:3.
- Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:328.
- Adams P, Altes A, Brissot P, et al. Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int 2018; 12:83.
- Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005; 352:1769.
|Section of the report||Action(s)||Concern(s)|
||Individuals may inadvertently provide the wrong name on a test sample. Testing should be done by a laboratory that can ensure that the identification matches the tested individual.|
||All actionable medical testing (eg, positive finding or negative finding in an individual suspected of having a genetic disorder) should be conducted in a CLIA-certified laboratory that has met appropriate quality standards for performing the specific test. Some direct-to-consumer testing is not performed in CLIA-certified laboratories and may lack appropriate quality controls.|
|Date of testing||
||Germline variants do not change over time. However, as new data become available, the classification of variant pathogenicity may change, especially for variants classified as VUS. Repeat testing may be considered, as the technologies for exome sequencing may improve and may identify a variant missed on a prior test.|
||Not all genetic testing panels are comprehensive in the genes or variants in those genes they evaluate. New disease genes or clinically important variants in existing genes may be identified through further research.|
||Not all methods will identify all variants. In some cases such as HFE testing, only one or two variants are clinically relevant, and sequencing of the entire coding region of the gene is not required, whereas in other conditions, limited testing for one or two variants may miss clinically important findings. Gene panels may be especially useful when multiple genes could potentially be responsible for a clinical phenotype.|
|Classification of pathogenicity||
||Interpretation of pathogenicity takes into account many data sources including laboratory research, research databases, population studies, and pedigree analyses. In some cases, pathogenicity is well established (eg, the variant that causes sickle cell disease); in others, it is more subjective and incomplete. Variants classified as VUS, likely benign, or benign generally are not actionable and should not impact medical interventions. Consulting a publicly curated database such as ClinVar or discussing the results with an expert in the specific disease, or referral to a clinical geneticist, genetic counselor, or disease expert may be helpful.|
* Indications for testing vary according to the individual's medical history, family history, and other factors such as desire for preconception counseling. In some cases, an individual who did not have a clinical indication for testing may have an unexpected finding from genetic testing that, if accurate, would indicate the need for an intervention, and such findings may be actionable regardless of the initial reasons for testing.
|HFE||AR||Classical hereditary hemochromatosis (HH) with low penetrance; clinical onset in adulthood|
|AR||Juvenile hemochromatosis with complete penetrance and early age of iron overload (childhood or young adulthood), along with early onset of hypogonadism and cardiac complications. Liver disease is less prominent.|
|TFR2 (transferrin receptor 2)||AR||Rare condition described in case reports. Clinically similar to classical HH but with onset in young adults.|
|SLC40A1 (ferroportin)||AD||Variable dominant disorder:
|Autosomal dominant||Pattern of inheritance that requires only one affected variant allele (a variant inherited from one parent or that arises de novo) to transmit the trait or risk of disease. Not sex-linked. First-degree relatives (siblings, children) have a 50% chance of sharing (or inheriting) the variant allele.|
|Autosomal recessive||Pattern of inheritance that generally requires both variants on both alleles (one from each parent) in order to transmit the trait or risk of disease. Not sex-linked. Individuals with one variant are sometimes called carriers.|
|Carrier||Individual who has a specific variant in one allele of the gene in their germline DNA (inherited from one parent or arising de novo). For recessive disorders, refers to a heterozygote who is generally (or mostly) unaffected. For dominant disorders, carriers are generally considered at risk for the disorder.|
|Expressivity||Differences in the severity of disease manifestations in individuals who share the same genotype (eg, cystic fibrosis is said to have variable expressivity because two individuals with the same genotype may have differences in the degree of pancreatic or lung dysfunction).|
|Genotyping||Determining the DNA sequence of a particular gene or portion of a gene in an individual. Can be done on DNA from sources such as nucleated epithelial cells from saliva, tumor cells from a biopsy, or WBCs from peripheral blood. Can be used to determine germline or somatic sequence, depending on the source of the cells.|
|Germline||Derived from the gametes (sperm or egg cells) and present in the early embryo; germline variants are typically present in all body cells and do not change. Germline variants can be passed down to subsequent generations.|
|Mutation||Term that may be used to describe changes in DNA or protein sequence compared with a reference sequence. The American College of Genetics and Genomics (ACMG) has expressed concern that this term can cause confusion or incorrect assumptions regarding pathogenicity, and the ACMG recommends that findings from genetic testing be described using the term "variant" with a qualifier regarding pathogenicity (or lack thereof).|
|Pathogenicity||Likelihood that a specific variant is capable of causing disease or conferring disease risk. Does not determine the likelihood that disease will occur (which depends on other factors such as disease penetrance). Refer to separate table in UpToDate for the categories.|
|Pedigree||Diagram of a family showing relationships among family members, sex of each family member, presence or absence of one or more genetic disorders, and often the age at which they manifested. Used in genetic counseling to identify possible inherited causes of disease and their inheritance patterns.|
|Penetrance||Likelihood that a person with a disease-associated variant will manifest one or more features of the disease. Many disease variants have incomplete or variable penetrance, meaning that not all individuals with the variant will manifest the associated disorder.|
|Somatic||Referring to tissues that are not within the germline. Variation that arises in somatic tissues is not passed from parent to offspring. Somatic mutations are common in cancer.|
|Variant||Change in the sequence of DNA compared with a reference sequence. Variants can be benign (associated with normal gene function), pathogenic (associated with altered gene function and/or clinical disease, also called mutations), or somewhere in between. The term polymorphism is often (but not exclusively) used for benign variants. Refer to a separate table in UpToDate that defines the categories.|
|VUS||Variant of uncertain significance (or unknown significance). Refers to a variant for which insufficient information is available to classify as benign or pathogenic.|
|Genotype||Risk for iron overload and its complications*||Testing/interventions|
|Negative for C282Y and H63DΔ||
* Complications of iron overload may include:
- Liver damage, which can progress to cirrhosis
- Cardiac toxicity, with heart failure and/or arrhythmias in severe cases
- Other endocrinopathies including hypopituitarism, hypogonadism, and hypothyroidism
- Skin pigmentation (bronze skin)
- Increased susceptibility to infection
- Multiple transfusions (more than 10 to 20 units)
- Thalassemia or other conditions with ineffective erythropoiesis
- Rare genetic conditions such as juvenile hemochromatosis
- Liver disease (alcohol or non-alcohol related)
- Any results that are obtained by direct-to-consumer testing or for a research study and that are considered clinically actionable should be repeated in a Clinical Laboratory Improvements Amendment (CLIA)-certified clinical laboratory with proper patient identification, review of the testing method, and review of the specific variant(s) tested.
- For individuals considered to be at risk for iron overload due to a positive family history or abnormal iron studies, any additional testing or interventions are done with shared decision-making with the tested individual and input from other treating clinicians.
- Repeat iron studies at a later date may be appropriate for individuals with an increased risk for iron overload who do not have evidence of iron overload when tested in young adulthood (<40 for men or before menopause for women).
* Generally includes testing for two variants, C282Y and H63D. Rarely, there may be a positive family history with a genetic cause other than HFE C282Y homozygosity or C282Y/H63D compound heterozygosity; in such cases it may be reasonable to test for the familial variant(s). If there is a family history of iron overload at a young age (<age 40 in men or in premenopausal women), it may be reasonable to test for other (non-HFE) hemochromatosis genes such as those discussed in UpToDate.
¶ Other reasons to perform iron studies include:
- Positive family history of iron overload not due to transfusions
- Multiple red blood cell (RBC) transfusions (more than 10 to 20 transfusions)
- Anemias due to ineffective erythropoiesis such as Thalassemia
- Increased hepatic transaminases
- Unexplained heart failure or endocrinopathy
- Suspected iron deficiency
Contributor DisclosuresClara Camaschella, MDGrant/Research/Clinical Trial Support: Vifor Pharma [Iron deficiency anemia (ferric carboxymaltose)]. Consultant/Advisory Boards: Celgene [Iron overload, thalassemia (Luspatercept)]; Novartis [Anemia of inflammation (CSJ137, anti-BMP6 antibody)].Meadow Heiman, MS, LCGC, CCRCNothing to discloseRobert T Means, Jr, MD, MACPNothing to discloseJennifer S Tirnauer, MDNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.