1. Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network
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Vaibhav Patel, Marc S. Williams, Gail P. Jarvik, Iftikhar J. Kullo, David Carrell, Zi Ye, Angelika Erwin, Marylyn D. Ritchie, S. Malia Fullerton, Elisha M. Friesema, Catherine A. McCarty, Agnes S. Sundaresan, Helena Kuivaniemi, Gabriella Papa, Kimberly Derr, Kris Hansen, Murray H. Brilliant, Sharon Aufox, Carlos J. Gallego, Joseph Bochenek, Amber A. Burt, Paul K. Crane, Sarah C. Stallings, Arno G. Motulsky, Jennifer A. Pacheco, Erwin P. Bottinger, Eric B. Larson, Gerard Tromp, Mariza de Andrade, Terrie Kitchner, David R. Crosslin, Dan M. Roden, Christopher G. Shaw, Brittany Knick Ragon, Maureen E. Smith, Joshua C. Denny, Omri Gottesman, and Glenn S. Gerhard
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Male ,Compound heterozygosity ,Gastroenterology ,Cohort Studies ,Liver disease ,0302 clinical medicine ,Genotype ,Genetics(clinical) ,030212 general & internal medicine ,Child ,Genetics (clinical) ,Genetics ,0303 health sciences ,medicine.diagnostic_test ,Homozygote ,Middle Aged ,Prognosis ,hereditary hemochromatosis ,Penetrance ,3. Good health ,multicenter cohort ,return of results ,Liver biopsy ,Hereditary hemochromatosis ,Cohort ,Female ,Adult ,Heterozygote ,medicine.medical_specialty ,Biology ,p.Cys282Tyr ,Article ,hemochromatosis ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,penetrance ,iron overload ,Hemochromatosis Protein ,Hemochromatosis ,Aged ,030304 developmental biology ,eMERGE Network ,Histocompatibility Antigens Class I ,Genetic Variation ,Membrane Proteins ,medicine.disease ,United States ,Amino Acid Substitution ,HFE ,Follow-Up Studies - 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.
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