Identification of Novel Mutations by Targeted NGS Panel in Patients with Hyperferritinemia.

BACKGROUND

Several inherited diseases cause hyperferritinemia with or without iron overload. Differential diagnosis is complex and requires an extensive work-up. Currently, a clinical-guided approach to genetic tests is performed based on gene-by-gene sequencing. Although reasonable, this approach is expensive and time-consuming and Next Generation Sequencing (NGS) technology may provide cheaper and quicker large-scale DNA sequencing.

METHODS

We analysed 36 patients with non--related hyperferritinemia. Liver iron concentration was measured in 33 by magnetic resonance. A panel of 25 iron related genes was designed using SureDesign software. Custom libraries were generated and then sequenced using Ion Torrent PGM.

RESULTS

We identified six novel mutations in , three novel and one known mutation in , one known mutation and a de-novo deletion in , and a novel mutation in in ten patients. In silico analyses supported the pathogenic role of the mutations.

CONCLUSIONS

Our results support the use of an NGS-based panel in selected patients with hyperferritinemia in a tertiary center for iron metabolism disorders. However, 26 out of 36 patients did not show genetic variants that can individually explain hyperferritinemia and/or iron overload suggesting the existence of other genetic defects or gene-gene and gene-environment interactions needing further studies.