BACKGROUND: p.C282Y mutation and rare variants in the HFE gene have been 
associated with hereditary hemochromatosis (HH). HH is also caused by mutations 
in other genes, such as the hemojuvelin (HJV), hepcidin (HAMP), transferrin 
receptor 2 (TFR2) and ferroportin (SLC40A1). The low rate homozygous p.C282Y 
mutation in Brazil is suggestive that mutations in non-HFE genes may be linked 
to HH phenotype.
AIM: To screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 
genes to characterize the molecular basis of HH in a sample of the Brazilian 
population.
MATERIALS AND METHODS: Fifty-one patients with primary iron overload 
(transferrin saturation ≥50% in females and ≥60% in males) were selected. 
Subsequent bidirectional DNA sequencing of HFE, HJV, HAMP, TFR2 and SLC40A1 
exons was performed.
RESULTS: Thirty-seven (72.5%) out of the 51 patients presented at least one HFE 
mutation. The most frequent genotype associated with HH was the homozygous 
p.C282Y mutation (n=11, 21.6%). In addition, heterozygous HFE p.S65C mutation 
was found in combination with p.H63D in two patients and homozygous HFE p.H63D 
was found in two patients as well. Sequencing in the HJV and HAMP genes revealed 
HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Molecular and 
clinical diagnosis of juvenile hemochromatosis (homozygous form for the HJV 
p.G320V) was described for the first time in Brazil. Three TFR2 polymorphisms 
(p.A75V, p.A617A and p.R752H) and six SLC40A1 polymorphisms (rs13008848, 
rs11568351, rs11568345, rs11568344, rs2304704, rs11568346) and the novel 
mutation SLC40A1 p.G204S were also found.
CONCLUSIONS: The HFE p.C282Y in homozygosity or in heterozygosity with p.H63D 
was the most frequent mutation associated with HH in this sample. The HJV 
p.E302K and HAMP p.R59G variants, and the novel SLC40A1 p.G204S mutation may 
also be linked to primary iron overload but their role in the pathophysiology of 
HH remain to be elucidated.