Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis

Abstract

Diagnostic genetic testing for hereditary hemochromatosis is readily available for clinically relevant HFE variants (i.e., those that generate the C282Y, H63D and S65C HFE polymorphisms); however, genetic testing for other known causes of iron overload, including mutations affecting genes encoding hemojuvelin, transferrin receptor 2, HAMP, and ferroportin is not. As an alternative to conventional genetic testing we propose diagnostic use of whole exome sequencing for characterization of non-HFE hemochromatosis. To illustrate the effectiveness of whole exome sequencing as a diagnostic tool, we present the case of an 18-year-old female with a probable case of juvenile hemochromatosis, who was referred for specialty care after testing negative for commonly occurring HFE variants. Whole exome sequencing offered complete coverage of target genes and is a fast, cost effective diagnostic tool for characterization of non-HFE hemochromatosis.

Appropriate Clinical Genetic Testing of Hemochromatosis Type 2–4, Including Ferroportin Disease

“… 16 WES also revealed a homozygous substitution in HJV from guanine to thymine in position 959, confirming WES validity in diagnosis of p.G320V hemochromatosis. 54 The second mutation in HJV identified by Papanikolaou et al was a substitution of thymine to adenine at position 665, known as p.I222N. 16 The p.I281T mutation has been detected both as a homozygous mutation in a Greek patient and as compound heterozygous with the nonsense mutation p.C321X in Chinese patients.…”

“… 57 It has been proposed that WES should be considered for a possible diagnosis of Type 2A HH only after demonstration of elevated ferritin and transferrin saturation, and negative HFE and p.G320V testing. 54 Classical symptoms of Type 2A HH accompanied by secondary hypothyroidism and iron overload in the pituitary may be due to a frameshift mutation from a cytosine deletion at position 697 of the HJV gene, resulting in a stop codon at amino acid 245 of HJV . 58 Commercially available testing for Type 2A HH includes single gene panels for p.G320V available from Fulgent 43 and Invitae; 44 exome sequencing available from Blueprint Genetics, 42 Prevention Genetics, 45 the Valencian Institute of Microbiology (Ivami) 46 and Invitae.…”

Hereditary Hemochromatosis

“…4. Whole-exome sequencing offered complete coverage of target genes and is a fast, costeffective diagnostic tool for characterization of non-HFE hemochromatosis (Farrell et al 2015). 8.…”