Genotype-phenotype relation within families with various forms of hereditary hemochromatosis

Hereditary Hemochromatosis (HH) is a genetic condition characterized by excess
iron absorption and pathologic iron deposition in tissue. Usual treatment
consists of the removal of body iron by phlebotomy treatments performed weekly
until iron parameters are normal, after which these parameters are maintained
at normal range by phlebotomies 2-8 times yearly. Hemochromatosis leads to
infertility, liver cirrhosis, diabetes, and mortality as a result of liver
cirrhosis or heart failure without treatment. If discovered before iron
deposition occurs, irreversible damage can be prevented by treatment
(phlebotomies).
The most important gene associated with hemochromatosis is the hemochromatosis
gene (HFE), which was identified in 1996. Homozygous C282Y-mutations or
compound heterozygosity C282Y/H63D is observed in 80-100% of patients with HH.
In recent years, other genes which code for proteins involved in the iron
metabolism have been discovered: hemojuvelin, (HJV), hepcidin (HAMP),
transferrin receptor 2 (TFR2), and ferroportin (SLC40A1). Mutations in these
genes are responsible for rare, non-HFE-related forms of HH.
The hemochromatosis family study (HEFAS, a multicentre study amongst 1st grade
relatives of patients with homozygous C282Y mutations in the HFE gene), amongst
others, showed that not all C282Y homozygotes developed iron deposition during
their lifetime. These differences are mainly unexplained. Almost certainly this
is the result of an interaction between the environment (the balance between
iron available from the diet and iron loss) and genes other than the HFE gene.
There have been reports of families with mutations in two genes, which are
involved in the iron metabolism. This is called digenic inheritance. The model
of digenic inheritance is mainly criticized because of the low number of
well-documented cases. We need to learn more about which genotypes
(combinations of mutations) predispose to iron loading to be able to develop an
effective strategy to identify people with an increased risk of iron overload.
Recently, we identified a combination of a new mutation in the hemojuvelin
(HJV) gene with the C282Y mutation in the HFE gene in an index patient with
juvenile hemochromatosis from a large family, with hemochromatosis in 4 large
sib ships. Furthermore, we collect index patients, where the HFE genotype does
not seem to explain the severity of the disease. Using cascade research, we
would like to collect a large pool of persons with different combinations of
genotypes to relate their genotypes to the severity of iron overload.
We now have the opportunity to study the different combinations of HJV and HFE
mutations in detail in different persons who vary in age. In the long run, this
research can provide important information about which genotypes are most
strongly associated with a predisposition for iron overload. Since it is
important for the participants to know whether they load iron, results of the
laboratory results on iron parameters and on genotype as well as an advice
based on these results will be reported to the general practitioner of the
patient, based on current standards (Health Council Report)

Which combinations of mutations in the HFE and HJV and other genes involved in
iron metabolism are associated to iron overload?

1. After deliberation with the proband, family members are informed in writing
(Appendix 1 *wervingsbrief HJV-HEFAS.doc*) and are invited to a meeting, in
which the background of the disease and the research is explained. Before this
meeting , they are asked to fill out a questionnaire and to sign the informed
consent (Appendix 2 *vragenlijstinformedconsentHEFASHJV.doc*). This
questionnaire was used before in the HEFAS (persons with the homozygous C282Y
mutation and their family members) and NBS (a survey of the general population
in the city of Nijmegen) investigations, facilitating comparison of the results
with other populations.
2. Questionnaires and informed consent are collected at the meeting. If the
informed consent permits it, blood (3x 10 ml) is drawn for the determination of
creatinin, LDH, CRP, hemocytometrics (to exclude pathologies that influence
iron parameters), iron and iron binding, ferritin, hepcidin and ALAT (a measure
for liver damage), and DNA to investigate the presence of mutations. Also, 10
ml of urine is collected for the determination of hepcidin and creatinin.
3. Results are reported to the general practitioner of the patient, with a
referral to a specialist of iron metabolism if applicable (Appendix 3
*UitslagbriefHA.doc*).

see ABR form