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

Wallace, Daniel F.  and Subramaniam, V. Nathan  (2016) The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genetics in Medicine, 18 6: 618-626. doi:10.1038/gim.2015.140


Author Wallace, Daniel F. 
Subramaniam, V. Nathan 
Title The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data
Formatted title
The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data
Journal name Genetics in Medicine   Check publisher's open access policy
ISSN 1530-0366
1098-3600
Publication date 2016-06-01
Year available 2015
Sub-type Article (original research)
DOI 10.1038/gim.2015.140
Open Access Status Not yet assessed
Volume 18
Issue 6
Start page 618
End page 626
Total pages 9
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Language eng
Subject 2716 Genetics (clinical)
Abstract 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.
Formatted abstract
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.
Keyword Hemochromatosis
Mutations
Next-generation sequencing
Non-HFE hemochromatosis
Prevalence
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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