DNA testing for haemochromatosis: diagnostic, predictive and screening implications

doi:10.1080/pat.32.4.274.279

Pathology

Volume 32, Issue 4, 2000, Pages 274-279

https://doi.org/10.1080/pat.32.4.274.279 Get rights and content

Summary

Since 1996, the identification of the HFE gene has enabled DNA testing for hereditary haemochromatosis (HH). The range of DNA testing available includes: (1) diagnostic, (2) predictive (also called presymptomatic testing) and (3) screening. Access to DNA testing has been facilitated by an Australian Medicare rebate, the first available for genetic disorders. Despite the availability of HFE DNA testing in HH, it remains necessary to interpret results in the context of the clinical picture. Traditional markers based on phenotype (transferrin saturation, ferritin and liver biopsy) are still required in some circumstances. We report our experience with HFE DNA testing using a semi-automated approach, which allows multiplexing for the two common mutations (C282Y and H63D). Screening a cohort of β-thalassaemia major and sickle cell anaemia patients of predominantly Mediterranean origin showed that these individuals do not have the common C282Y mutation. This excluded C282Y as a factor in the pathogenesis of iron overload in these haemoglobinopathies. It also showed that the C282Y mutation is of limited value when investigating HH in certain ethnic groups. An Australian family studied illustrated the relative contribution of C282Y and H63D in iron overload. A recently reported third mutation (S65C) in the HFE gene was detected in a low frequency in the populations tested.

References (19)

A. Roetto et al.
Juvenile hemochromatosis locus maps to chromosome 1q
Am J Hum Genet
(1999)
C. Mura et al.
HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild forms of hemochromatosis
Blood
(1999)
B.R. Bacon et al.
Molecular medicine and hemochromatosis: at the crossroads
Gastroenterology
(1999)
DHG Crawford et al.
Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation
Gastroenterology
(1998)
C. Niederau et al.
Long-term survival in patients with hereditary hemochromatosis
Gastroenterology
(1996)
Online Mendelian Inheritance in Man, OMIM™. Johns Hopkins University, Baltimore, MD. MIM number: 235200; last edited...
J.N. Feder et al.
A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis
Nat Genet
(1996)
W. Burke et al.
Hereditary hemochromatosis. Gene discovery and its implications for population screening
J Am Med Assoc
(1998)
W. Burke et al.
Hemochromatosis: genetics helps to define a multifactorial disease
Clin Genet
(1998)

There are more references available in the full text version of this article.

Cited by (8)

Morbidity risk in HFE associated hereditary hemochromatosis C282Y heterozygotes
2002, Toxicology
Citation Excerpt :
Disease prevention and health promotion, if performed scientifically and carefully, can greatly reduce medical care costs and increase the averages persons's productivity and sense of well being. There is considerable debate within the medical community of the relative merits of widespread population screening using the C282Y mutation to detect preclinically those who are homozygous for C282Y and so at considerable risk for developing HHC (Allen and Williamson, 1999; Trent et al., 2000; Rossi et al., 2001; Lyon and Frank, 2001). Currently, population screening for HFE mutations is not accepted by public health officials (Dooley and Walker, 2000), largely, because of unresolved financial, ethical, legal, and also for some scientific reasons e.g. the variability of disease penetrance in genetically susceptible patients.
Hereditary hemochromatosis (HHC) is a late-onset, autosomal recessive disorder leading to a chronic iron overload syndrome, finally causing diabetes, cardiomyopathy and liver disease. HHC is the most common single gene disorder in northern Europeans that occurs with a frequency of approximately 0.5%, and most of these patients carry the C282Y and H63D mutation in the HFE gene on chromosome 6p21.3. The vast majority of HHC patients are homozygous for the C282Y mutation, but HHC phenotypes are observed in other genotypes. Expression of the disease, in those homozygous for the C282Y mutation, is highly variable depending on the various features of the population studied. C282Y heterozygotes have slightly increased iron stores and in absence of other genetic and/or environmental factors do usually not develop the HHC phenotype. It is currently a matter of debate whether C282Y heterozygotes may have an increased risk for morbidity. Different studies investigating the association of C282Y heterozygocity with morbidity have given conflicting results, as is exemplified by extrahepatic cancers, cardiovascular diseases, alcoholic liver disease, and diabetes. However, there are examples of clear and unambiguous disease associations, such as with sporadic pophyria cutanea tarda. It remains to be seen whether a strong correlation between the C282Y heterozygous state and distinct pathological conditions will exist and large-scale genotyping studies will help to identify such potential risk groups in the future.
Effect of hereditary hemochromatosis gene H63D and C282Y mutations on iron overload in sickle cell disease patients
2016, Turkish Journal of Hematology
Genotype-specific signal generation based on digestion of 3-way DNA junctions: Application to KRAS variation detection
2006, Clinical Chemistry
Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: New epidemiological data
2005, BMC Medical Genetics
Mutations in the HFE gene in patients with rheumatic diseases
2005, Casopis Lekaru Ceskych
Frequency of HFE gene mutations in Iranian beta-thalassaemia minor patients
2003, European Journal of Haematology

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DNA testing for haemochromatosis: diagnostic, predictive and screening implications

Summary

Am J Hum Genet

Blood

Gastroenterology

Gastroenterology

Gastroenterology

A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis

Nat Genet

Hereditary hemochromatosis. Gene discovery and its implications for population screening

J Am Med Assoc

Hemochromatosis: genetics helps to define a multifactorial disease

Clin Genet