Hereditary Hemochromatosis via the TFR2 Gene

TFR2-related hereditary hemochromatosis (TFR2-HCC) is a disorder characterized by excess iron overload due to increased intestinal iron absorption. Symptom onset primarily occurs after the second decade of life with fatigue and arthralgia being initial signs of disease. TFR2-HCC, if untreated, can result in advanced disease including hepatomegaly, hepatic cirrhosis, hypogonadism, diabetes, arthritis, and cardiomyopathy. To date, less than 50 cases of TFR2-HCC have been reported with disease primarily occurring in patients of Japanese and Italian descent (Camaschella 2011). There are six types of hemochromatosis each due to a different genetic cause: type 1- HFE, type 2- HAMP or HJV/HFE2, type 3- TFR2, type 4- SLC40A1, type 5- FTH1, and type 6- FTL. Type 1 hemochromatosis is the most prevalent form of the disease and represents >90% of cases (Vujic 2014). Genetic testing can be helpful in differential diagnosis of HH from other liver function disorders and for determining the underlying cause of hemochromatosis (Zarrilli et al. 2013). Phlebotomy is standard treatment to reduce serum iron levels and prevent progressive liver damage.

Hemochromatosis is inherited in an autosomal recessive mode through pathogenic variants in the HFE, HAMP, HFE2/HJV, or TFR2 genes or an autosomal dominant pattern through pathogenic variants in the SLC40A1, FTH1, or FTL genes (Santos et al. 2012). The c.313C>T (p.Arg105*), c.515T>A (p.Met172Lys), c.750C>G (p.Tyr250*), c.88dupC (p.Arg30Profs*31), and c.1861_1872del (p.Ala621_Gln624del) variants account for nearly half of TFR2-HCC cases (Camaschella et al. 2000; Le Gac et al. 2004; Roetto et al. 2001; Camaschella 2011). Missense and nonsense pathogenic variants have been reported throughout the coding region in the TFR2 gene. Indels, splice site alterations have also been seen in only a few individuals. There is no clear genotype/phenotype correlation, and penetrance is variable (Camaschella 2011; Bardou-Jacquet et al. 2013). Co-occurrence of HFE and TFR2 pathogenic variants has been reported in patients with TFR2-HCC (Roetto et al. 2001; Pietrangelo et al. 2005). The TFR2 gene encodes the transferrin receptor 2 protein that is primarily expressed in hepatocytes. The transferrin receptor 2 protein regulates hepcidin levels, which are responsible for controlling intestinal iron absorption (Robb and Wesslin-Resnick 2004).

Analytical sensitivity should be high because all pathogenic variants reported to date are detectable by sequencing. Clinical sensitivity cannot be estimated because only a small number of patients have been reported.

This test provides full coverage of all coding exons of the TFR2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.