The Clinical Relevance of Compound Heterozygosity for the C282Y and H63D Substitutions in Hemochromatosis

Walsh, Alissa J.; Dixon, Jeannette L.; Ramm, Grant A.; Hewett, David G.; Lincoln, Doug; Anderson, Gregory J.; Subramaniam, V. Nathan; Dodemaide, Julian; Cavanaugh, Juleen A.; Bassett, Mark L.; Powell, Lawrie W.

doi:10.1016/j.cgh.2006.07.009

Cited by 100 publications

(74 citation statements)

References 37 publications

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“…It is noteworthy that studies in different ethnic populations have demonstrated that prevalence of steatosis in African-American patients is much lower compared with Hispanic or non-Hispanic white patients diagnosed with metabolic syndrome, suggesting an involvement of additional factors, besides those associated with the metabolic syndrome, in determining the development of NAFLD (Caldwell et al, 2007). In this regard, carriers of variant alleles of the hemochromatosis (HFE) gene (Valenti et al, 2003;Walsh et al, 2006), the PPAR␥ coactivator-1, sterol regulatory element-binding protein gene-1 (Eberlé et al, 2004), hepatic lipase (Stefan et al, 2005), and mitochondrial triglyceride transfer protein (MTP) (Gambino et al, 2007) were proposed to be at added risk for NAFLD (Pessayre, 2007).…”

Section: Introduction: Hepatic Steatosis-a Common Road With Differmentioning

confidence: 99%

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

Anderson

Borlak²

2008

Pharmacol Rev

342

255

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Section: Introduction: Hepatic Steatosis-a Common Road With Differmentioning

confidence: 99%

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

Anderson

Borlak²

2008

Pharmacol Rev

342

255

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“…First, other HFE genotypes, including the compound heterozygote encoding the Cys282Tyr and His63Asp mutations, have been associated with an HH phenotype, although individuals with such genotypes accumulate less iron than Cys282Tyr homozygotes (1)(2)(3). Other rare private HFE mutations responsible for HH have also been reported.…”

mentioning

confidence: 99%

Global Sequencing Approach for Characterizing the Molecular Background of Hereditary Iron Disorders

Cunat¹,

Giansily‐Blaizot²,

Bismuth³

et al. 2007

Clinical Chemistry

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Background: New genetic forms of hereditary hemochromatosis (HH) or hereditary hyperferritinemia (HF)have been identified over the last few years, and abnormalities of various genes may interact in a single patient. This study aimed to develop a rapid automated method for sequencing the main genes involved. Methods: We used a standard 96-well microplate with a single PCR condition in an adaptation of the SCAIP (single-condition amplification with internal primer) method to sequence the HFE (hemochromatosis), HAMP (hepcidin antimicrobial peptide), HFE2/HJV [hemochromatosis type 2 (juvenile)], SLC40A1 (ferroportin), and TFR2 (transferrin receptor 2) genes, and the 5 untranslated region of the FTL (ferritin, light polypeptide) gene. To further simplify the method, we adjusted PCR conditions to avoid the use of an internal primer and applied this single-condition amplification method to 38 selected, unrelated patients. We tailored the genetic investigation according to the clinical picture, with the patients falling into 2 groups. Group 1 consisted of patients with hyperferritinemia and high transferrin saturation (TS) (classic adult and juvenile HH forms, groups 1A and 1B, respectively), and group 2 consisted of patients with hyperferritinemia and low, typical, or

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“…36 For example, the p.His63Asp and p.Ser65Cys variants in HFE are known to contribute to some cases of iron overload but have a much lower penetrance than p.Cys282Tyr. 7,8 We decided to exclude these variants from our analysis so as not to over inflate population prevalence estimates.…”

Section: Discussionmentioning

confidence: 99%

“…7 However, the penetrance of this genotype is low, and other cofactors that contribute to iron overload are usually present. 8 Much of the knowledge we have gained regarding the molecular mechanisms regulating iron homeostasis has stemmed from the identification and characterization of genes implicated in non-HFE forms of iron overload. Central to the regulation of systemic iron homeostasis is the hepcidin-ferroportin axis.…”

Section: Introductionmentioning

confidence: 99%

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

Wallace

Subramaniam

2016

Genetics in Medicine

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Purpose:The prevalence of HFE-related hereditary hemochromatosis (HH) among European populations has been well studied. There are no prevalence data for atypical forms of HH caused by mutations in HFE2, HAMP, TFR2, or SLC40A1. The purpose of this study was to estimate the population prevalence of these non-HFE forms of HH.Methods: A list of HH pathogenic variants in publically available next-generation sequence (NGS) databases was compiled and allele frequencies were determined.Results: Of 161 variants previously associated with HH, 43 were represented among the NGS data sets; an additional 40 unreported functional variants also were identified. The predicted prevalence of HFE HH and the p.Cys282Tyr mutation closely matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2-, and HAMP-related forms are predicted to be rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. Significantly, SLC40A1 variants that have been previously associated with autosomal-dominant ferroportin disease were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. Conclusion:We have, for the first time, estimated the population prevalence of non-HFE HH. This methodology could be applied to estimate the population prevalence of a wide variety of genetic disorders.

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The Clinical Relevance of Compound Heterozygosity for the C282Y and H63D Substitutions in Hemochromatosis

Cited by 100 publications

References 37 publications

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

Global Sequencing Approach for Characterizing the Molecular Background of Hereditary Iron Disorders

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

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