Hereditary Hemochromatosis (HH) is a genetically heterogeneous disorder caused 
by mutations in at least five different genes (HFE, HJV, TFR2, SLC40A1, HAMP) 
involved in the production or activity of the liver hormone hepcidin, a key 
regulator of systemic iron homeostasis. Nevertheless, patients with an HH-like 
phenotype that remains completely/partially unexplained despite extensive 
sequencing of known genes are not infrequently seen at referral centers, 
suggesting a role of still unknown genetic factors. A compelling candidate is 
Bone Morphogenetic Protein 6 (BMP6), which acts as a major activator of the 
BMP-SMAD signaling pathway, ultimately leading to the upregulation of hepcidin 
gene transcription. A recent seminal study by French authors has described three 
heterozygous missense mutations in BMP6 associated with mild to moderate 
late-onset iron overload (IO). Using an updated next-generation sequencing 
(NGS)-based genetic test in IO patients negative for the classical HFE 
p.Cys282Tyr mutation, we found three BMP6 heterozygous missense mutations in 
four patients from three different families. One mutation (p.Leu96Pro) has 
already been described and proven to be functional. The other two (p.Glu112Gln, 
p.Arg257His) were novel, and both were located in the pro-peptide domain known 
to be crucial for appropriate BMP6 processing and secretion. In silico modeling 
also showed results consistent with their pathogenetic role. The patients' 
clinical phenotypes were similar to that of other patients with BMP6-related IO 
recently described. Our results independently add further evidence to the role 
of BMP6 mutations as likely contributing factors to late-onset moderate IO 
unrelated to mutations in the established five HH genes.