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Am J Hum Genet. 2015 Oct 1;97(4):512-20. doi: 10.1016/j.ajhg.2015.08.008. Epub 2015 Sep 10.

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network.

Author information

1
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle, WA 98195, USA. Electronic address: cgallego@med.umich.edu.
2
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
3
Center for Health Research, Geisinger Health System, Danville, PA 17822, USA.
4
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
5
Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA.
6
Department of Bioethics and Humanities, University of Washington, Seattle, WA 98195, USA.
7
Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
8
Siegfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA.
9
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
10
Research Division, Essentia Institute of Rural Health, Duluth, MN 55805, USA.
11
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA.
12
Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.
13
Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
14
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
15
Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
16
Division of General Internal Medicine and Geriatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
17
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
18
Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA.
19
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
20
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
21
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
22
Genomic Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
23
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: gjarvik@medicine.washington.edu.

Abstract

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.

KEYWORDS:

HFE; eMERGE Network; hemochromatosis; hereditary hemochromatosis; iron overload; multicenter cohort; p.Cys282Tyr; penetrance; return of results

PMID:
26365338
PMCID:
PMC4596892
DOI:
10.1016/j.ajhg.2015.08.008
[Indexed for MEDLINE]
Free PMC Article

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