Background:
More than 80% of patients with hemochromatosis are homozygous for the p.Cys282Tyr
mutation in the HFE gene. Recent studies have shown that even by comprehensive genetic
testing using next generation sequencing methods, only a minority of patients with
suspected non- HFE hemochromatosis harbor disease-causing mutations in HAMP, HJV, HFE, TFR2 or SLC40A1. The aim of the present study was to determine the prevalence of mutations in HFE and non-HFE hemochromatosis genes in a cohort of patients with hyperferritinemia.
Methods:
Between September 2007 and November 2017 410 patients were referred for the evaluation
of high serum ferritin to our outpatient liver clinic. This retrospective analysis
included the results from comprehensive clinical and biochemical workup including
non-invasive assessment of parenchymal iron in liver spleen and pancreas by R2* mapping.
Results:
Forty-one (10%) patients were homozygous for the p.Cys282Tyr mutation in HFE. From all other patients, 199 had confirmed hepatic iron overload, of whom 38 patients
had given their written informed consent for further genetic testing by full exome
sequencing. Potentially disease-causing mutations were identified in 16 (42%) patients.
When ferritin, transferrin saturation, liver and spleen R2*, plasma hepcidin concentration
and CRP were included as continuous variables in a multivariable binary logistic regression
analysis none were independently associated with the presence of non-HFE mutations.
However, low to normal spleen iron defined as a spleen R2* < 60 s-1 was significantly associated with the presence of non-HFE mutations (OR 7.56, p = 0.009).
Conclusion:
In conclusion, our study shows that full exome sequencing has a high pre-test likelihood
for the genetic diagnosis of non-HFE hemochromatosis in patients with hepatic iron
overload and low to normal spleen iron concentration.
