Rare HFE variants are the most frequent cause of hemochromatosis in non‐c282y homozygous patients with hemochromatosis

Hamdi-Rozé, Houda; Beaumont-Epinette, Marie-Pascale; Ali, Zeineb Ben; Lan, Caroline Le; Loustaud‐Ratti, Véronique; Causse, Xavier; Loréal, Olivier; Deugnier, Yves; Brissot, Pierre; Jouanolle, Anne–Marie; Bardou-Jacquet, Édouard

doi:10.1002/ajh.24535

Cited by 18 publications

(13 citation statements)

References 17 publications

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“…The HFE gene was first identified by Feder and colleagues more than two decades ago after a prodigious and costly effort in positional cloning . While mutations in this gene remain the most common cause of hereditary haemochromatosis (known as Type 1 or HFE ‐related haemochromatosis), pathogenic mutations in other genes have since been discovered to cause or contribute to the disease (Table ). These include mutations in HJV and HAMP genes (coding for haemojuvelin and hepcidin respectively) in juvenile (Type 2) haemochromatosis, which present a more severe phenotype with a much earlier manifestation of the disease.…”

Section: Role Of Genetic Variationmentioning

confidence: 99%

Haemochromatosis: a clinical update for the practising physician

Radford-Smith

Powell

2018

Internal Medicine Journal

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Haemochromatosis is most commonly due to the autosomal recessive inheritance of a C282Y substitution in the HFE protein, whereby both alleles of the corresponding gene are affected. The disease is characterised by an inappropriate increase in intestinal iron absorption due to reduced expression of the iron regulatory protein, hepcidin. Progressive iron deposition in parenchymal tissues may ultimately lead to liver and other organ toxicity. The characteristic biochemical abnormalities are raised serum ferritin and transferrin saturation, which can be used in conjunction with genetic tests and emerging magnetic resonance imaging-based techniques to diagnose patients with the disorder. Progressive iron overload can manifest clinically as advanced fibrosis, cirrhosis and hepatocellular carcinoma. Enigmatically, the penetrance of both raised iron indices and clinically significant disease is incomplete in patients with hereditary haemochromatosis. Regardless, advanced clinical presentations of the disease have become less common due to increased awareness and earlier diagnosis. On the other hand, obesity and alcohol have been identified as major risk factors that can compound the risk of liver injury in people with hereditary (HFE) haemochromatosis. The prospect of modifying genes that may contribute to the clinical expression of the disease is the subject of ongoing research. Treatment with phlebotomy remains the first-line therapy, and if instigated early leads to a normal life expectancy. A healthy, well-balanced diet is recommended to be incorporated as part of the ongoing management of the disease.

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Section: Role Of Genetic Variationmentioning

confidence: 99%

Haemochromatosis: a clinical update for the practising physician

Radford-Smith

Powell

2018

Internal Medicine Journal

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“…A limitation of our method is that it is limited to the analysis of the recurrent H63D and C282Y HFE mutations while clinical mutations in HFE and other genes have also been reported in patients with iron overload, albeit less frequently (28,30). Another limitation of our assay is that it is based on PCR, which is susceptible to allele dropout caused by polymorphisms; however, we minimized the chances of assay interference by incorporating mixed bases in locations of known SNPs (rs570212174 and rs376650371) in the primers (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Multiplex Allele-Specific PCR for Simultaneous Detection of H63D and C282Y HFE Mutations in Hereditary Hemochromatosis

Arts

Waye

2018

The Journal of Applied Laboratory Medicine

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Background Hereditary hemochromatosis (HH) is characterized by excessive iron absorption in the intestine, which can lead to failure of vital organs such as the heart, liver, and pancreas. Among northern Europeans, HH is most often associated with the C282Y and H63D mutations of the HFE gene. We developed a test that allows screening for both mutations in a single reaction. Methods A multiplex allele-specific PCR was developed for simultaneous genotyping of the H63D and C282Y HFE mutations. PCR fragments were designed such that the resulting PCR product can be analyzed in a single polyacrylamide gel lane. Results Test results from our multiplex assay were concordant with genotypes of 55 Canadian patients with suspected hemochromatosis, which had previously been established by allele-specific PCRs that targeted H63D and C282Y in separate reactions. Conclusions Molecular diagnostic detection of H63D and C282Y mutations can be achieved by a variety of methods, but these are not necessarily time-efficient or economical. Multiplex allele-specific PCR is an excellent tool for molecular diagnostic screening for H63D and C282Y mutations in patients with suspected hemochromatosis. This method is inexpensive, accurate, and highly efficient in terms of labor, throughput, and turnaround time.

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“…11,12 Rare subtypes of haemochromatosis present a particular challenge. 13,14 Examples of extremely rare diseases include storage diseases, such as lysosomal acid lipase (LAL) deficiency, 15,16 a genetic disorder characterised by a deficiency of the lysosomal acid lipase (LIPA or LAL) enzyme, and hereditary cholestatic disease caused by a deficiency of biliary transporters (PFIC diseases). In such conditions the challenge of clinician awareness is added to the challenges and anxieties around achieving a genetic diagnosis.…”

Section: Key Pointmentioning

confidence: 99%

Access to care in rare liver diseases: New challenges and new opportunities

Jones

Sturm

Lohse

2018

Journal of Hepatology

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Patients with rare diseases are often disadvantaged, particularly those with rare liver diseases. Reasons for disadvantage include delayed or overlooked diagnosis, lack of local expertise and high-quality care, poor scientific understanding of the disease process and limited therapeutic options. In adult liver disease this can be compounded by prejudices towards patients with liver disease in general, because of a perception (incorrect for all rare liver diseases) that liver disease is lifestyle related and thus "self-inflicted". In paediatric rare liver diseases, such as biliary atresia, optimising outcomes requires a particularly timely diagnosis. Irrespective of patient age, the scientific and medical community must rise to the challenge of advancing our understanding of rare liver disease, searching for more effective and specific therapies, and providing the infrastructure to provide the best care for all patients, infants, children, young and older adults. The European Reference Network for Rare Liver Diseases is an important step in this direction.

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Rare HFE variants are the most frequent cause of hemochromatosis in non‐c282y homozygous patients with hemochromatosis

Cited by 18 publications

References 17 publications

Haemochromatosis: a clinical update for the practising physician

Haemochromatosis: a clinical update for the practising physician

Multiplex Allele-Specific PCR for Simultaneous Detection of H63D and C282Y HFE Mutations in Hereditary Hemochromatosis

Access to care in rare liver diseases: New challenges and new opportunities

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