The Invitae Hereditary Hemochromatosis Panel analyzes five genes associated with hereditary hemochromatosis (HH), a genetic disorder that causes increased iron absorption and can lead to iron overload. These genes were curated, based on the available evidence to date, to provide a comprehensive test for indications related to hemochromatosis-related iron overload.
HAMP HFE HJV SLC40A1 TFR2
HAMP HFE HJV SLC40A1 TFR2
Hereditary hemochromatosis (HH) is a genetic condition that affects iron metabolism. It is characterized by an increase in iron absorption by different organs, including the liver, pancreas, heart, and skin, and it may result in iron overload in these tissues. Symptoms of this condition are a result of the iron overload, coupled with the body’s inability to naturally get rid of the excess iron. Early symptoms of HH are often nonspecific and may consist of joint pain, fatigue, loss of appetite, or reduced sex drive. However, people with HH more commonly present with biochemical signs of increased iron absorption (i.e., increased levels of serum ferritin and/or transferrin saturation). Over time, this biochemical profile may lead to iron overload in different organ systems, which may cause clinical signs such as liver disease, diabetes, skin discoloration, heart conditions, or arthritis. The features of HH may be influenced by environmental factors like alcohol use, vitamin C intake, the amount of iron in the diet, and exposure to certain types of bacteria.
Approximately 60% to 90% of patients with hereditary hemochromatosis (HH) have homozygous or compound heterozygous pathogenic variants in the gene HFE, but clinical sensitivity can be dependent on associated symptoms. In patients with juvenile forms of hemochromatosis, disease-causing variants are found in HJV at a rate of 90%. Pathogenic variants in HAMP are found less frequently—fewer than 10% of juvenile cases. Digenic inheritance has also been reported in the majority of the HH-related genes. The frequency of pathogenic variants in TFR2 and SLC40A1 is unknown, though patients with a dominant family history are more likely to have an identifiable SLC40A1 variant than those without a family history. Population studies on the prevalence of pathogenic variants in these genes is currently lacking, which makes it difficult to accurately estimate the clinical sensitivity.
HH is inherited in an autosomal recessive pattern, except for the subtype hemochromatosis type 4, which is autosomal dominant.
In general, HH type 1 is a low penetrance condition. Of the individuals who are homozygous for the specific pathogenic variant C282Y, 38% to 50% may develop biochemical signs of iron overload, but only 10% to 33% will go on to develop clinical symptoms of hemochromatosis. More men than women develop these symptoms due to the monthly elimination of iron that women experience through menstruation. The average age of onset in men occurs between 40 and 70 years of age while the majority of women do not present until after menopause.
HH types 2A and 2B, the juvenile forms of hemochromatosis caused by pathogenic variants in HJV (also known as HFE2) and HAMP, have a relatively high but incomplete penetrance. Juvenile HH is associated with an early age of onset (typically before the age of 30), along with a more severe clinical course compared to that seen in other forms of HH. Males and females are equally affected, but there is variable expressivity in terms of symptom severity and age of onset.
HH type 3 has high variability in terms of clinical expression and age of onset. Some patients present early in life, similar to juvenile HH, while others present later in adulthood. HH type 3 is characterized by a slower disease progression and a less severe clinical course compared to juvenile HH—though it is generally more severe than HH type 1. Type 3 frequently presents with arthropathy; occasionally, there is cardiac and endocrine involvement. Its exact penetrance is unknown. This type seems to be most common in those of Italian or Japanese ancestry, but is generally thought to be rare in all populations.
HH type 4 has high but incomplete penetrance. The typical age of onset is in adulthood and the clinical symptoms are relatively mild, similar to what is seen in type 1.
HH is the most common autosomal recessive genetic condition; it is also the most commonly inherited liver disease among Caucasians (particularly in those of northern European descent). Overall prevalence is usually reported as 1 in 250 individuals, with the highest prevalence in Northern European countries. Prevalence of HH in Asian and African countries is low, though large studies of non-HFE HH (i.e., HH that is not a result of a variant in the HFE gene) are lacking. The vast majority of Caucasians who are affected have the most common HH-causing genetic variant, which is associated with HH type 1 (HFE gene). All forms of HH other than type 1 are thought to be very rare (at least clinically), with each type’s prevalence estimated at fewer than 1 individual in 100,000.
Candidates for HH testing include those with:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|