Clinical evaluation of a hemochromatosis next-generation sequencing gene panel

Background Next-generation sequencing of an iron metabolism gene panel could identify pathogenic mutations, improving on standard hemochromatosis genetic testing and providing a molecular diagnosis in patients with suspected iron overload. Methods A next-generation sequencing panel of 15 genes with known roles in iron metabolism was constructed. 190 patients were sequenced: 94 from a tertiary hemochromatosis clinic, and 96 submitted for HFE testing with biochemical evidence of iron overload [elevated ferritin (>450 μg/L) or transferrin saturation (>55%)] obtained from a chart review. Results From the hemochromatosis clinic cohort, 6 patients were diagnosed with non-HFE hemochromatosis due to homozygous hemojuvelin (HFE2) mutations. Ten additional heterozygous pathogenic mutations were observed. From the chart review cohort, a C-terminus ferritin light chain (FTL) frameshift mutation was observed consistent with neuroferritinopathy. Heterozygous deletion of HFE2, and 4 additional rare pathogenic or likely pathogenic heterozygous mutations were identified in 7 patients. Conclusions An iron metabolism gene panel provided a molecular diagnosis in 6 patients with non-HFE iron overload, and is suitable for diagnostic purposes in exceptional cases in specialized clinics. Further research will be required to assess the modifier effect of rare heterozygous mutations in iron metabolism genes. This article is protected by copyright. All rights reserved.