Juvenile Hereditary Hemochromatosis via the HFE2 (HJV) Gene

Juvenile hereditary hemochromatosis (JHH) is a disorder characterized by excess iron overload with symptoms presenting within the first or second decade of life. Initial symptoms include lack of appetite, fatigue, amenorrhea, and arthralgia. Chronic iron deposition can lead to advanced disease including hypogonadotropic hypogonadism, hepatomegaly, cirrhosis, cardiomyopathy, arthropathy, and osteoporosis. In severe cases, JHH has led to lethal cardiac disease. Glucose intolerance has also been reported in about half of JHH cases. Early diagnosis of JHH is important as phlebotomy may be used to reduce iron levels and greatly reduces morbidity and mortality (Goldberg 2011; Lanzara et al. 2004; Santos et al. 2012).

There are six types of hemochromatosis each due to a different genetic cause: type 1- HFE, type 2- HAMP or HFE2/HJV, type 3- TRF2, type 4- SLC40A1, type 5- FTH1, and type 6- FTL. Hemochromatosis is inherited in an autosomal recessive mode through pathogenic variants in the HFE, HAMP, HFE2/HJV, or TRF2 genes or an autosomal dominant pattern through pathogenic variants in the SLC40A1, FTH1, or FTL genes (Santos et al. 2012). Missense variants occurring in exons 3 and 4 of the HFE2/HJV gene are the most commonly reported pathogenic variants, with the c.959G>T (p.Gly320Val) variant being seen in greater than half of JHH cases. Small insertions and deletions have also been reported (Lanzara et al. 2004; Papanikolaou et al. 2003; Lee et al. 2004). No splice site alterations or gross deletions have been documented in the HFE2/HJV gene. Penetrance for JHH is greatly elevated compared to hereditary hemochromatosis via pathogenic variants in the HFE gene (Goldberg 2011). The HFE2/HJV gene encodes the protein hemojuvelin, which maintains iron hemostasis by inducing expression of the negative iron regulating protein, hepcidin (Lin et al. 2007).

In a series of 34 patients with JHH, pathogenic variants in the HFE2/HJV were found in all cases (Lanzara et al. 2004). However, additional reports have suggest that pathogenic variants in the HAMP gene occur in >10% of JHH patients (Goldberg 2011). Analytical sensitivity should be high as all pathogenic variants in the HFE2/HJV gene reported to date are detectable by sequencing.

This test provides full coverage of all coding exons of the HFE2/HJV gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.