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

Carlos J. Gallego, Amber Burt, Agnes S. Sundaresan, Zi Ye, Christopher Shaw, David R. Crosslin, Paul K. Crane, S. Malia Fullerton, Kris Hansen, David Carrell, Helena Kuivaniemi, Kimberly Derr, Mariza De Andrade, Catherine A. McCarty, Terrie E. Kitchner, Brittany K. Ragon, Sarah C. Stallings, Gabriella Papa, Joseph Bochenek, Maureen E. SmithSharon A. Aufox, Jennifer A. Pacheco, Vaibhav Patel, Elisha M. Friesema, Angelika Ludtke Erwin, Omri Gottesman, Glenn S. Gerhard, Marylyn Ritchie, Arno G. Motulsky, Iftikhar J. Kullo, Eric B. Larson, Gerard Tromp, Murray H. Brilliant, Erwin Bottinger, Joshua C. Denny, Dan M. Roden, Marc S. Williams, Gail P. Jarvik

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)512-520
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 2015

Bibliographical note

Funding Information:
The eMERGE Network was initiated and funded by the National Human Genome Research Institute (NHGRI) through the following grants: U01HG006828 (Cincinnati Children’s Hospital Medical Center and Boston Children’s Hospital), U01HG006830 (Children’s Hospital of Philadelphia), U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University), U01HG006382 (Geisinger Clinic), U01HG006375 (Group Health Cooperative and the University of Washington), U01HG006379 (Mayo Clinic), U01HG006380 (Icahn School of Medicine at Mount Sinai), U01HG006388 (Northwestern University), U01HG006378 (Vanderbilt University Medical Center), and U01HG006385 (Vanderbilt University Medical Center serving as the coordinating center). G.P.J. was supported by grant 5T32GM007454 from the National Institute of General Medical Sciences and grants U01HG0006507 and U01HG007307 from the NHGRI and National Cancer Institute. C.J.G. was supported by grant K12 HS021686 from the Patient-Centered Outcomes Research Career Development Program of the Agency for Healthcare Research and Quality.

Publisher Copyright:
© 2015 The Authors.


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


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