title: Clinical evaluation of a hemochromatosis next-generation sequencing gene panel.
abstract: 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. A total of 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, six 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 four additional rare pathogenic or likely pathogenic heterozygous mutations were identified in seven patients.
  
  
  CONCLUSIONS
  An iron metabolism gene panel provided a molecular diagnosis in six 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.
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Matthew B
authors.identifier: http://orcid.org/0000-0002-5750-6286
authors.initials: MB
authors.lastname: Lanktree
authors.affiliation: Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
authors.forename: Bekim
authors.initials: B
authors.lastname: Sadikovic
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: John S
authors.initials: JS
authors.lastname: Waye
authors.affiliation: Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Levstik
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Bruce B
authors.initials: BB
authors.lastname: Lanktree
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Jovana
authors.initials: J
authors.lastname: Yudin
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Crowther
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pare
authors.affiliation: Department of Medicine, Western University, London, ON, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Adams
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D015415:Biomarkers; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006432:Hemochromatosis / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D018962:Phlebotomy; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007501:Iron
keywords: hemochromatosis; iron overload; neuroferritinopathy; next-generation sequencing