Hereditary Hemochromatosis Panel

Hereditary Hemochromatosis (HH) is a disorder characterized by excess iron overload, which, if untreated, can lead to progressive and potentially fatal organ dysfunction. Chronic iron deposition can result in liver cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes, fatigue, and hypogonadism. There are six types of hemochromatosis, each due to a different genetic cause: type 1- HFE, type 2- HAMP or HFE2/HJV, type 3- TFR2, type 4- SLC40A1, type 5- FTH1, and type 6- FTL (Santos et al. 2012). Penetrance of type I HH is variable with many individuals remaining asymptomatic. Disease onset typically occurs after the fourth decade of life with penetrance for type I HH being influenced by other factors including alcohol consumption, fatty liver disease, and co-occurring pathogenic variants in other hemochromatosis related genes (Andersen et al. 2004). Type II HH, also referred to as juvenile HH, is a more severe form of disease with symptom onset occurring with the first or second decade of life. Phlebotomy is the standard treatment for HH and can minimize iron deposition leading to chronic disease. Genetic testing is helpful in the differential diagnosis of HH from other disorders presenting with iron overload including thalassemia, hemolytic anemia, chronic liver disease, and aceruloplasminemia (Bacon et al 2011).

Hemochromatosis is inherited in an autosomal recessive manner through pathogenic variants in the HFE, HAMP, HFE2/HJV, or TFR2 genes or an autosomal dominant manner through pathogenic variants in the SLC40A1, FTH1, or FTL genes (Santos et al. 2012). Type I HH is the most common form. In patients identified with type I HH via transferring saturation analysis, 60% of patients are homozygous for c.845G>A (p.Cys282Tyr), 8% homozygous for c.187C>G (p.His63Asp), and 7% compound heterozygous for these two variants in the HFE gene (de Villiers et al. 1999; Stuhrmann et al. 2010). Co-occurring pathogenic variants in the HAMP and HFE2/HJV genes have been reported in individuals with more severe forms of type I HH (Jacolot et al. 2004; Le Gac et al. 2004). Other forms of HH exhibit higher but variable penetrance for disease compared to type I HH. See individual test descriptions for additional information on the molecular biology of each gene.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Analytical sensitivity for detection of causative variants in the HFE gene is >95% as gross gene deletions have been reported in very few cases (Le Gac et al. 2008). HJV, HAMP, SLC40A1, TFR2, FTH1, and FTL analytical sensitivity is >99%. In patients where type I HH is clearly defined and other causes of iron overload have been ruled out, clinical sensitivity is >90% in Northern Europeans (Bryant et al. 2008). In a series of 34 patients with juvenile HH, pathogenic variants in HFE2/HJV were found in all cases (Lanzara et al. 2004). However, additional reports suggest that pathogenic variants in the HAMP gene occur in >10% of juvenile HH patients (Goldberg 2011). Clinical sensitivity for the TFR2, FTH1, and FTL genes is currently unknown due to the small number of patients reported to date.