title: Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network.
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.
authors.affiliation: 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.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Gallego
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Burt
authors.affiliation: Center for Health Research, Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Agnes S
authors.initials: AS
authors.lastname: Sundaresan
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Zi
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Shaw
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Department of Bioethics and Humanities, University of Washington, Seattle, WA 98195, USA.
authors.forename: S Malia
authors.initials: SM
authors.lastname: Fullerton
authors.affiliation: Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
authors.forename: Kris
authors.initials: K
authors.lastname: Hansen
authors.affiliation: Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.affiliation: Siegfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: Siegfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Derr
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Research Division, Essentia Institute of Rural Health, Duluth, MN 55805, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Kitchner
authors.affiliation: Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Brittany K
authors.initials: BK
authors.lastname: Ragon
authors.affiliation: Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Stallings
authors.affiliation: Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Papa
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bochenek
authors.affiliation: Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Smith
authors.affiliation: Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Aufox
authors.affiliation: Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pacheco
authors.affiliation: Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Patel
authors.affiliation: Division of General Internal Medicine and Geriatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Elisha M
authors.initials: EM
authors.lastname: Friesema
authors.affiliation: Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Angelika Ludtke
authors.initials: AL
authors.lastname: Erwin
authors.affiliation: Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Omri
authors.initials: O
authors.lastname: Gottesman
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Marylyn
authors.initials: M
authors.lastname: Ritchie
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Arno G
authors.initials: AG
authors.lastname: Motulsky
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.affiliation: Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Siegfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA.
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Erwin
authors.initials: E
authors.lastname: Bottinger
authors.affiliation: 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.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Genomic Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Williams
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: gjarvik@medicine.washington.edu.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002648:Child; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006432:Hemochromatosis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D019683:Penetrance; D011379:Prognosis; D014481:United States / Q000453:epidemiology
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins
keywords: HFE; eMERGE Network; hemochromatosis; hereditary hemochromatosis; iron overload; multicenter cohort; p.Cys282Tyr; penetrance; return of results