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

Wallace, Daniel F.; Subramaniam, V. Nathan

doi:10.1038/gim.2015.140

Cited by 61 publications

(50 citation statements)

References 42 publications

(47 reference statements)

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“…However, non‐ HFE HH mutations are exceedingly rare. A survey of public next‐generation sequencing data reported the cumulative pathogenic allele frequency of HFE2, TFR2, and HAMP mutations as between 0.00007 and 0.0005, yielding a combined expected prevalence of <1 in 1 000 000 . Moreover, the patients with homozygous HFE2 mutations included here displayed severe phenotypes, clearly recognized as having iron overload in a tertiary care hemochromatosis clinic.…”

Section: Discussionmentioning

confidence: 87%

Clinical evaluation of a hemochromatosis next‐generation sequencing gene panel

Lanktree

Sadiković

Waye

et al. 2016

European J of Haematology

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Section: Discussionmentioning

confidence: 87%

Clinical evaluation of a hemochromatosis next‐generation sequencing gene panel

Lanktree

Sadiković

Waye

et al. 2016

European J of Haematology

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“…not reported in the following databases: dbSNPs ( http://www.ncbi.nlm.nih.gov/SNP/), 1,000 genome ( http://www.1000 genomes.org/category/sequence), OMIM ( http://www.ncbi.nlm.nih.gov/omim), and ESP Databases (http://evs.gs.washington.edu/EVS/). We also checked a very recent paper reporting a catalogue of all hemochromatosis associated variants . Two out of the new mutations, i.e.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload

et al. 2016

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Hereditary hemochromatosis, one of the commonest genetic disorder in Caucasians, is mainly associated to homozygosity for the C282Y mutation in the HFE gene, which is highly prevalent (allele frequency up to near 10% in Northern Europe) and easily detectable through a widely available "first level" molecular test. However, in certain geographical regions like the Mediterranean area, up to 30% of patients with a HH phenotype has a negative or non-diagnostic (i.e. simple heterozygosity) test, because of a known heterogeneity involving at least four other genes (HAMP, HJV, TFR2, and SLC40A1). Mutations in such genes are generally rare/private, making the diagnosis of atypical HH essentially a matter of exclusion in clinical practice (from here the term of "non-HFE" HH), unless cumbersome traditional sequencing is applied. We developed a Next Generation Sequencing (NGS)-based test targeting the five HH genes, and applied it to patients with clinically relevant iron overload (IO) and a non-diagnostic first level genetic test. We identified several mutations, some of which were novel (i.e. HFE W163X, HAMP R59X, and TFR2 D555N) and allowed molecular reclassification of "non-HFE" HH clinical diagnosis, particularly in some highly selected IO patients without concurring acquired risk factors. This NGS-based "second level" genetic test may represent a useful tool for molecular diagnosis of HH in patients in whom HH phenotype remains unexplained after the search of common HFE mutations.

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“…The gnomAD database contains variant frequencies derived from the whole exome or whole genome sequencing of over 120,000 people, from eight ethnic subgroups. NGS datasets are valuable resources and have been used by us and others for estimating the population prevalence of genetic diseases, such as HFE and non-HFE hemochromatosis [11] and primary ubiquinone deficiency [12]. A recent study, that was published while this article was in preparation, used the gnomAD dataset to predict the prevalence of WD [13].…”

Section: Introductionmentioning

confidence: 99%

ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease

Wallace

Dooley

2018

Preprint

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AbstractWilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the copper transporting P-type ATPase gene ATP7B. Estimates for WD population prevalence vary with 1 in 30,000 generally quoted. However, some genetic studies have reported much higher prevalence rates. The aim of this study was to estimate the population prevalence of WD and the pathogenicity/penetrance of WD variants by determining the frequency of ATP7B variants in a genomic sequence database. A catalogue of WD-associated ATP7B variants was constructed and then frequency information for these was extracted from the gnomAD dataset. Pathogenicity of variants was assessed by (a) comparing gnomAD allele frequencies against the number of reports for variants in the WD literature and (b) using variant effect prediction algorithms. 231 WD-associated ATP7B variants were identified in the gnomAD dataset, giving an initial estimated population prevalence of around 1 in 2400. After exclusion of WD-associated ATP7B variants with predicted low penetrance, the revised estimate showed a prevalence of around 1 in 20,000, with higher rates in the Asian and Ashkenazi Jewish populations. Reanalysis of other recent genetic studies using our penetrance criteria also predicted lower population prevalences for WD in the UK and France than had been reported. Our results suggest that differences in variant penetrance can explain the discrepancy between reported epidemiological and genetic prevalences of WD. They also highlight the challenge in defining penetrance when assigning causality to some ATP7B variants.

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

Cited by 61 publications

References 42 publications

Clinical evaluation of a hemochromatosis next‐generation sequencing gene panel

Clinical evaluation of a hemochromatosis next‐generation sequencing gene panel

Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload

ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease

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