Biallelic STAB1 pathogenic variants cause hereditary hyperferritinemia

Serum ferritin measurement is a routine laboratory test to indirectly evaluate body iron content. However, many additional factors may elevate serum ferritin levels disproportionally to iron stores. Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. Despite the long history of clinical use, fundamental aspects of the biology of serum ferritin are still unclear. We studied eleven healthy subjects from eight different families presenting unexplained hyperferritinemia without iron overload. To detect the genetic cause of hyperferritinemia we carried out whole-exome sequencing. Immunohistochemistry and flow cytometry assays were performed on patient liver biopsies and monocyte-macrophages to confirm the pathogenic role of the identified candidate variants. Through a combined approach of whole-exome sequencing and homozygosity mapping, we found biallelic candidate STAB1 variants in ten subjects from seven families. STAB1 encodes the multifunctional scavenger receptor stabilin-1. Immunohistochemical studies and flow cytometry analyses showed absent or markedly reduced stabilin-1 in patient liver samples, monocytes and monocyte-derived macrophages. We present biallelic STAB1 mutations as a new cause of inherited hyperferritinemia without iron overload suggesting the existence of new and unexpected function of stabilin-1 in ferritin metabolism. In conclusion, our findings strongly support biallelic STAB1 mutations as a novel genetic cause of inherited hyperferritinemia without iron overload and suggest the existence of a new and unexpected function of stabilin-1 in ferritin metabolism.