An HFE Intronic Variant Promotes Misdiagnosis of Hereditary Hemochromatosis

Somerville, Martin J.; Sprysak, Kathleen A.; Hicks, Matt; Elyas, Basil G.; Vicen-Wyhony, Leanne M.

doi:10.1086/302550

Cited by 43 publications

(26 citation statements)

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“…This may result in the incorrect assignment of homozygosity for C282Y. 66,67 However, under suitable PCR conditions this does not occur and the validity of previous publications is not compromised by this polymorphism. 68 It is clearly desirable to remove this potential cause of mis-typing by selecting alternative primers.…”

Section: A Pcr Artefact?mentioning

confidence: 99%

What is the role of genetic testing in diagnosis of haemochromatosis?

Worwood

2001

Ann Clin Biochem

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Section: A Pcr Artefact?mentioning

confidence: 99%

What is the role of genetic testing in diagnosis of haemochromatosis?

Worwood

2001

Ann Clin Biochem

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“…Homozygotes and heterozygotes for each of these variants, as well as compound heterozygotes for both, can be readily identified. However, there may be overdiagnosis of C282Y homozygotes in some laboratories owing to the presence of a common, innocuous DNA polymorphism near the mutation that may interfere with the polymerase chain reaction (28,45). A reevaluation of C282Y mutation testing in a large number of laboratories (9,32) failed to show the excess of homozygotes, which presumably can be accounted for by inappropriate conditions for the polymerase chain reaction.…”

Section: Testing Considerationsmentioning

confidence: 99%

Population Screening in Hereditary Hemochromatosis

Motulsky

Beutler

2000

Annu. Rev. Public Health

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▪ Abstract Hemochromatosis is a common autosomal recessive condition found in the homozygous state in 1/200–1/400 people of northern-, central-, and western-European origin. It causes increased iron storage, which may lead to liver cirrhosis, liver cancer, heart disease, arthritis, and diabetes in many but not all affected adults, with a higher frequency in males. The condition is easily treated by repeated venesections without side effects but is frequently overlooked. Population screening of adults using iron indices alone or combined with DNA testing has therefore been recommended, but a consensus conference in 1997 recommended that such screening be deferred, owing to uncertainty regarding the extent of clinical disease that may develop in individuals detected by such programs. There was also concern that DNA screening results might be used for discrimination in insurance and occupational settings. Screening family members of patients with evidence of definite iron loading, however, is accepted by all observers. Because serious complications may be overlooked, a more aggressive stance toward case detection in the adult population has been advocated by some observers, realizing that unnecessary treatment might occur. Because additional information regarding the spectrum of clinical disease in homozygotes in now accumulating, a consensus conference in the near future is suggested to consider appropriate policies.

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“…Other groups from different institutions independently reported that the sam e polym orphism interfered with the RsaI genotype assay, although in a smaller num ber of patients (Table 1). One of these initially questioned the validity of the assay in two apparent C282Y homozygous siblings when two instances of nonpaternity were required to explain the results of the family studies (Somerville et al, 1999). Another group identified three C282Y heterozygous patients who had previously been incorrectly labeled as C282Y homozygotes by the RsaI assay when a confirmatory DNA sequence assay was performed on a num- ber of these same patients and discordant results were found (Mamotte et al, 1998).…”

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Pitfalls in the Genetic Diagnosis of Hereditary Hemochromatosis

Jeffrey

Adams

2000

Genetic Testing

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The widespread use of the genotype assay that identifies the common C282Y mutation in the HFE gene has allowed an earlier diagnosis to be made in many subjects. A significant number of these patients may have no evidence of phenotypic disease and have a normal serum ferritin level. This phenomenon is more common when the genotype assay is used to screen populations rather than higher-risk groups such as family members of a proband with hereditary hemochromatosis. Moreover, patients with significant iron overload may be wild type for the C282Y mutation and have no other demonstrable mutation of the HFE gene. The HFE genotype assay has recently been found to give a false-positive C282Y homozygous result in half of the subjects in one population screening study due to the presence of a single nucleotide polymorphism (SNP) that interfered with primer binding in the PCR assay. The problem may be overcome by using alternate primers. A number of other groups have confirmed the finding but in a much smaller number of subjects, whereas others found that their assays were not affected by the SNP. The use of the HFE genotype assay as the sole diagnostic criterion for hereditary hemochromatosis is not recommended. The genotype assay should be used as an adjunct to the established methods of demonstrating iron overload and be viewed as a predictor of either the presence of iron overload or the subsequent development of iron overload during an individual's lifetime.

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An HFE Intronic Variant Promotes Misdiagnosis of Hereditary Hemochromatosis

Cited by 43 publications

References 5 publications

What is the role of genetic testing in diagnosis of haemochromatosis?

What is the role of genetic testing in diagnosis of haemochromatosis?

Population Screening in Hereditary Hemochromatosis

Pitfalls in the Genetic Diagnosis of Hereditary Hemochromatosis

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