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1. Returning integrated genomic risk and clinical recommendations: the eMERGE study

Author

Jodell E. Linder, Aimee Allworth, Sarah T. Bland, Pedro J. Caraballo, Rex L. Chisholm, Ellen Wright Clayton, David R. Crosslin, Ozan Dikilitas, Alanna DiVietro, Edward D. Esplin, Sophie Forman, Robert R. Freimuth, Adam S. Gordon, Richard Green, Maegan V. Harden, Ingrid A. Holm, Gail P. Jarvik, Elizabeth W. Karlson, Sofia Labrecque, Niall J. Lennon, Nita A. Limdi, Kathleen F. Mittendorf, Shawn N. Murphy, Lori Orlando, Cynthia A. Prows, Luke V. Rasmussen, Laura Rasmussen-Torvik, Robb Rowley, Konrad Teodor Sawicki, Tara Schmidlen, Shannon Terek, David Veenstra, Digna R. Velez Edwards, Devin Absher, Noura S. Abul-Husn, Jorge Alsip, Hana Bangash, Mark Beasley, Jennifer E. Below, Eta S. Berner, James Booth, Wendy K. Chung, James J. Cimino, John Connolly, Patrick Davis, Beth Devine, Stephanie M. Fullerton, Candace Guiducci, Melissa L. Habrat, Heather Hain, Hakon Hakonarson, Margaret Harr, Eden Haverfield, Valentina Hernandez, Christin Hoell, Martha Horike-Pyne, George Hripcsak, Marguerite R. Irvin, Christopher Kachulis, Dean Karavite, Eimear E. Kenny, Atlas Khan, Krzysztof Kiryluk, Bruce Korf, Leah Kottyan, Iftikhar J. Kullo, Katie Larkin, Cong Liu, Edyta Malolepsza, Teri A. Manolio, Thomas May, Elizabeth M. McNally, Frank Mentch, Alexandra Miller, Sean D. Mooney, Priyanka Murali, Brenda Mutai, Naveen Muthu, Bahram Namjou, Emma F. Perez, Megan J. Puckelwartz, Tejinder Rakhra-Burris, Dan M. Roden, Elisabeth A. Rosenthal, Seyedmohammad Saadatagah, Maya Sabatello, Dan J. Schaid, Baergen Schultz, Lynn Seabolt, Gabriel Q. Shaibi, Richard R. Sharp, Brian Shirts, Maureen E. Smith, Jordan W. Smoller, Rene Sterling, Sabrina A. Suckiel, Jeritt Thayer, Hemant K. Tiwari, Susan B. Trinidad, Theresa Walunas, Wei-Qi Wei, Quinn S. Wells, Chunhua Weng, Georgia L. Wiesner, Ken Wiley, Josh F. Peterson, Adam Gordon, Agboade Sobowale, Akshar Patel, Alanna Strong, Alborz Sherafati, Alborz Sherfati, Alex Bick, Alka Chandel, Alyssa Rosenthal, Amit Khera, Amy Kontorovich, Andrew Beck, Andy Beck, Angelica Espinoza, Anna Lewis, Anya Prince, Ayuko Iverson, Bahram Namjou Khales, Barbara Benoit, Becca Hernan, Ben Kallman, Ben Kerman, Ben Shoemaker, Benjamin Satterfield, Bethany Etheridge, Blake Goff, Bob Freimuth, Bob Grundmeier, Brenae Collier, Brett Harnett, Brian Chang, Brian Piening, Brittney Davis, Candace Patterson, Carmen Demetriou, Casey Ta, Catherine Hammack, Catrina Nelson, Caytie Gascoigne, Chad Dorn, Chad Moretz, Chris Kachulis, Christie Hoell, Christine Cowles, Christoph Lange, Cindy Prows, Cole Brokamp, Courtney Scherr, Crystal Gonzalez, Cynthia Ramirez, Daichi Shimbo, Dan Roden, Daniel Schaid, Dave Kaufman, David Crosslin, David Kochan, Davinder Singh, Debbie Abrams, Digna Velez Edwards, Eduardo Morales, Edward Esplin, Ehsan Alipour, Eimear Kenny, Elisabeth Rosenthal, Eliza Duvall, Elizabeth McNally, Elizabeth Bhoj, Elizabeth Cohn, Elizabeth Hibler, Elizabeth Karlson, Ellen Clayton, Emily Chesnut, Emily DeFranco, Emily Gallagher, Emily Soper, Emma Perez, Erin Cash, Eta Berner, Fei Wang, Firas Wehbe, Francisco Ricci, Gabriel Shaibi, Gail Jarvik, George Hahn, Georgia Wiesner, Gillian Belbin, Gio Davogustto, Girish Nadkarni, Haijun Qiu, Hannah Beasley, Hao Liu, Heide Aungst, Hemant Tiwari, Hillary Duckham, Hope Thomas, Iftikhar Kullo, Ingrid Holm, Isabelle Allen, Iuliana Ionita-Laza, Jacklyn Hellwege, Jacob Petrzelka, Jacqueline Odgis, Jahnavi Narula, Jake Petrzelka, Jalpa Patel, James Cimino, James Meigs, James Snyder, Janet Olson, Janet Zahner, Jeff Pennington, Jen Pacheco, Jennifer Allen Pacheco, Jennifer Morse, Jeremy Corsmo, Jim Cimino, Jingheng Chen, Jocelyn Fournier, Jodell Jackson, Joe Glessner, Joel Pacyna, Johanna Smith, John Lynch, John Shelley, Jonathan Mosley, Jordan Nestor, Jordan Smoller, Joseph Kannry, Joseph Sutton, Josh Peterson, Joshua Smith, Julia Galasso, Julia Smith, Julia Wynn, Justin Gundelach, Justin Starren, Karmel Choi, Kate Mittendorf, Katherine Anderson, Katherine Bonini, Kathleen Leppig, Kathleen Muenzen, Kelsey Stuttgen, Kenny Nguyen, Kevin Dufendach, Kiley Atkins, Konrad Sawicki, Kristjan Norland, Laura Beskow, Li Hsu, Lifeng Tian, Lisa Mahanta, Lisa Martin, Lisa Wang, Lizbeth Gomez, Lorenzo Thompson, Lucas Richter, Luke Rasmussen, Lynn Petukhova, Madison O’Brien, Maegan Harden, Malia Fullerton, Marta Guindo, Martha Horike, Marwah Abdalla, Marwan Hamed, Mary Beth Terry, Mary Maradik, Matt Wyatt, Matthew Davis, Matthew Lebo, Maureen Smith, Maya del Rosario, Meckenzie Behr, Meg Roy-Puckelwartz, Mel Habrat, Melanie Myers, Meliha Yetisgen, Merve Iris, Michael DaSilva, Michael Preuss, Michelle McGowan, Mingjian Shi, Minoli Perera, Minta Thomas, Mitch Elkind, Mohammad Abbass, Mohammad Saadatagah, Molly Hess, Molly Maradik, Nataraja 'RJ' Vaitinadin, Nataraja Vaitinadin, Neil Netherly, Niall Lennon, Ning Shang, Nita Limdi, Noah Forrest, Noheli Romero, Nora Robinson, Noura Abul-Husn, Omar Elsekaily, Patricia Kovatch, Paul Appelbaum, Paul Francaviglia, Paul O’Reilly, Paulette Chandler, Pedro Caraballo, Peter Tarczy-Hornoch, Pierre Shum, Priya Marathe, Qiping Feng, Quinn Wells, Rachel Atchley, Radhika Narla, Rene Barton, Rex Chisholm, Richard Sharp, Riki Peters, Rita Kukafka, Robert Freimuth, Robert Green, Robert Winter, Roger Mueller, Ruth Loos, Ryan Irvin, Sabrina Suckiel, Sajjad Hussain, Samer Sharba, Sandy Aronson, Sarah Jones, Sarah Knerr, Scott Nigbur, Scott Weiss, Sean Mooney, Sharon Aufox, Sharon Nirenberg, Shawn Murphy, Sheila O’Byrne, Shing Wang (Sam) Choi, Sienna Aguilar, S.T. Bland, Stefanie Rodrigues, Stephanie Ledbetter, Stephanie Rutledge, Stuart James Booth, Su Xian, Susan Brown Trinidad, Suzanne Bakken, Teri Manolio, Tesfaye Mersha, Thevaa Chandereng, Tian Ge, Todd Edwards, Tom Kaszemacher, Valerie Willis, Vemi Desai, Vimi Desai, Virginia Lorenzi, Vivian Gainer, Wendy Chung, Wu-Chen Su, Xiao Chang, Yiqing Zhao, Yuan Luo, and Yufeng Shen

Subjects
Genetics (clinical)
Abstract

Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.Return of a novel report for communicating monogenic, polygenic, and family history based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Published
2022

3. Large-scale, three-dimensional tissue cytometry of the human kidney: a complete and accessible pipeline

Author

Michael J. Ferkowicz, Seth Winfree, Angela R. Sabo, Malgorzata M. Kamocka, Suraj Khochare, Daria Barwinska, Michael T. Eadon, Ying-Hua Cheng, Carrie L. Phillips, Timothy A. Sutton, Katherine J. Kelly, Pierre C. Dagher, Tarek M. El-Achkar, Kenneth W. Dunn, Richard Knight, Stewart Lecker, Isaac Stillman, Gearoid Mcmahon, Sus Waikar, Astrid Weins, Nir Hacohen, Paul Hoover, Mark Aulisio, Leslie Cooperman, Leal Herlitz, John O'toole, Emilio Poggio, John Sedor, Paul Appelbaum, Jonathan Barasch, Andrew Bomback, Vivette D'agati, Krzysztof Kiryluk, Karla Mehl, Ning (Sunny) Shang, Chenhua Weng, Laura Barisoni, Theodore Alexandrov, Tarek Ashkar, Pierre Dagher, Kenneth Dunn, Michael Eadon, Michael Ferkowicz, Katherine Kelly, Timothy Sutton, Steven Menez, Chirag Parikh, Avi Rosenberg, Pam Villalobos, Alison Slack, Sylvia Rosas, Mark Williams, Evren Azeloglu, Cijang (John) He, Ravi Iyengar, Samir Parikh, Chris Anderton, Ljiljana Pasa-Tolic, Dusan Velickovic, George (Holt) Oliver, Joseph Ardayfio, Jack Bebiak, Keith Brown, Taneisha Campbell, Catherine Campbell, Lynda Hayashi, Nichole Jefferson, Robert Koewler, Glenda Roberts, John Saul, Anna Shpigel, Edith Christine Stutzke, Lorenda Wright, Leslie Miegs, Roy Pinkeney, Rachel Sealfon, Olga Troyanskaya, Katherine Tuttle, Yury Goltsev, Blue Lake, Kun Zhang, Dejan Dobi, Maria Joanes, Zoltan Laszik, Garry Nolan, Andrew Schroeder, Ulysses Balis, Oliver He, Jeffrey Hodgin, Matthias Kretzler, Laura Mariani, Rajasree Menon, Edgar Otto, Jennifer Schaub, Becky Steck, Michele Elder, Daniel Hall, John Kellum, Mary Kruth, Raghav Murugan, Paul Palevsky, Parmjeet Randhawa, Matthew Rosengart, Sunny Sims-Lucas, Mary Stefanick, Stacy Stull, Mitchell Tublin, Charles Alpers, Ian De Boer, Malia Fullerton, Jonathan Himmelfarb, Robyn Mcclelland, Sean Mooney, Stuart Shankland, Kayleen Williams, Kristina Blank, Ashveena Dighe, Jonas Carson, Frederick Dowd, Zach Drager, Kumar Sharma, Guanshi Zhang, Asra Kermani, Simon Lee, Christopher Lu, Tyler Miller, Orson Moe, Harold Park, Kamalanathan Sambandam, Francisco Sanchez, Jose Torrealba, Toto Robert, Miguel Vazquez, Nancy Wang, Joe Gaut, Sanjay Jain, Anitha Vijayan, Randy Luciano, Dennis Moledina, Ugwuowo Ugochukwu, and Francis Perry Wilson

Subjects
0301 basic medicine, Computer science, Confocal, Cytological Techniques, Context (language use), Kidney, Article, Pathology and Forensic Medicine, law.invention, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Imaging, Three-Dimensional, Confocal microscopy, law, Microscopy, medicine, Humans, Image analysis, Molecular Biology, Fluorescent Dyes, Microscopy, Confocal, medicine.diagnostic_test, Cell Biology, Autofluorescence, 030104 developmental biology, Microscopy, Fluorescence, Multiphoton, 030220 oncology & carcinogenesis, Cytometry, Software, Biomedical engineering
Abstract

The advent of personalized medicine has driven the development of novel approaches for obtaining detailed cellular and molecular information from clinical tissue samples. Tissue cytometry is a promising new technique that can be used to enumerate and characterize each cell in a tissue and, unlike flow cytometry and other single-cell techniques, does so in the context of the intact tissue, preserving spatial information that is frequently crucial to understanding a cell’s physiology, function, and behavior. However, the wide-scale adoption of tissue cytometry as a research tool has been limited by the fact that published examples utilize specialized techniques that are beyond the capabilities of most laboratories. Here we describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues. In this workflow, multiphoton microscopy of unlabeled tissue is first conducted to collect autofluorescence and second-harmonic images. The tissue is then labeled with eight fluorescent probes, and imaged using spectral confocal microscopy. The raw 16-channel images are spectrally deconvolved into 8-channel images, and analyzed using the Volumetric Tissue Exploration and Analysis (VTEA) software developed by our group. We applied this workflow to analyze millimeter-scale tissue samples obtained from human nephrectomies and from renal biopsies from individuals diagnosed with diabetic nephropathy, generating a quantitative census of tens of thousands of cells in each. Such analyses can provide useful insights that can be linked to the biology or pathology of kidney disease. The approach utilizes common laboratory techniques, is compatible with most commercially-available confocal microscope systems and all image and data analysis is conducted using the VTEA image analysis software, which is available as a plug-in for ImageJ. Tissue cytometry is a promising new microscopy technique that can be used to enumerate and characterize each cell in a tissue. Here the authors describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues.

Published
2020

4. Familial identification: population structure and relationship distinguishability.

Author

Rori V Rohlfs, Stephanie Malia Fullerton, and Bruce S Weir

Subjects
Genetics, QH426-470
Abstract

With the expansion of offender/arrestee DNA profile databases, genetic forensic identification has become commonplace in the United States criminal justice system. Implementation of familial searching has been proposed to extend forensic identification to family members of individuals with profiles in offender/arrestee DNA databases. In familial searching, a partial genetic profile match between a database entrant and a crime scene sample is used to implicate genetic relatives of the database entrant as potential sources of the crime scene sample. In addition to concerns regarding civil liberties, familial searching poses unanswered statistical questions. In this study, we define confidence intervals on estimated likelihood ratios for familial identification. Using these confidence intervals, we consider familial searching in a structured population. We show that relatives and unrelated individuals from population samples with lower gene diversity over the loci considered are less distinguishable. We also consider cases where the most appropriate population sample for individuals considered is unknown. We find that as a less appropriate population sample, and thus allele frequency distribution, is assumed, relatives and unrelated individuals become more difficult to distinguish. In addition, we show that relationship distinguishability increases with the number of markers considered, but decreases for more distant genetic familial relationships. All of these results indicate that caution is warranted in the application of familial searching in structured populations, such as in the United States.

Published
2012
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5. When Participants in Genomic Research Grow Up: Contact and Consent at the Age of Majority

Author

Kyle B. Brothers, Ingrid A. Holm, Janet E. Childerhose, Armand H.M. Antommaria, Barbara A. Bernhardt, Ellen Wright Clayton, Bruce D. Gelb, Steven Joffe, John A. Lynch, Jennifer B. McCormick, Laurence B. McCullough, D. Williams Parsons, Agnes S. Sundaresan, Wendy A. Wolf, Joon-Ho Yu, Benjamin S. Wilfond, Benjamin E. Berkman, Leslie G. Biesecker, Sara C. Hull, Sawona Biswas, Wendy K. Chung, Barbara Koenig, Lisa S. Lehmann, Michelle Lewis, Amy L. McGuire, Melody J. Slashinski, Lainie F. Ross, Joseph S. Salama, Debra Skinner, Holly K. Tabor, Susan M. Wolf, Cassandra Perry, Ariel Chandler, Beth Cobb, John Harley, Melanie Myers, Rosetta Chiavacci, John Connolly, Andy Faucett, Samantha Fetterolf, David Ledbetter, Janet Williams, Kelly Ehrlich, Malia Fullerton, Kelly Hansen, Andrea Hartzler, Aaron Scrol, Lucy Carruth, Elizabeth Chau, Chris Chute, Iftikhar Kullo, Richard Sharp, Murray Brilliant, Norm Frost, Terrie Kitchner, Cathy McCarty, Kadija Ferryman, Carol Horowitz, Yolanda Keppel, Rosamond Rhodes, Saskia Sanderson, Randi Zinberg, Sharon Aufox, Michael Heathcote, Vivian Pan, Maureen Smith, Nanibaa' Garrison, Melissa Basford, Jacqueline Kirby, Mollie Bodin Claar, Lauren Melancon, and Sarah Stallings

Subjects
0301 basic medicine, medicine.medical_specialty, Biomedical Research, Informed Consent, Extramural, business.industry, Research Subjects, Genomic research, MEDLINE, Age Factors, Genomics, 030105 genetics & heredity, Institutional review board, Article, 03 medical and health sciences, Young Adult, Age of majority, Informed consent, Family medicine, Pediatrics, Perinatology and Child Health, medicine, Humans, Young adult, business, Child
Published
2015

6. Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes

Author

Bryan A. Comstock, David L. Veenstra, Peter Tarczy-Hornoch, S. Malia Fullerton, Robin L. Bennett, Deborah A. Nickerson, Carlos J. Gallego, Wylie Burke, Caroline S. Bennette, Martha Horike-Pyne, Patrick J. Heagerty, Susan Brown Trinidad, Laura M. Amendola, Dean A. Regier, Michael O. Dorschner, Gail P. Jarvik, Fuki M. Hisama, Donald L. Patrick, and William M. Grady

Subjects
Research design, medicine.medical_specialty, Pathology, Comparative Effectiveness Research, Cost-Benefit Analysis, Comparative effectiveness research, Article, law.invention, Randomized controlled trial, law, medicine, Humans, Pharmacology (medical), Exome, Genetic Predisposition to Disease, Precision Medicine, Intensive care medicine, Exome sequencing, business.industry, High-Throughput Nucleotide Sequencing, General Medicine, Sequence Analysis, DNA, Precision medicine, Colorectal Neoplasms, Hereditary Nonpolyposis, Adenomatous Polyposis Coli, Research Design, Outcomes research, business, Return of results, Colorectal Neoplasms
Abstract

Whole exome and whole genome sequencing are applications of next generation sequencing transforming clinical care, but there is little evidence whether these tests improve patient outcomes or if they are cost effective compared to current standard of care. These gaps in knowledge can be addressed by comparative effectiveness and patient-centered outcomes research. We designed a randomized controlled trial that incorporates these research methods to evaluate whole exome sequencing compared to usual care in patients being evaluated for hereditary colorectal cancer and polyposis syndromes. Approximately 220 patients will be randomized and followed for 12 months after return of genomic findings. Patients will receive findings associated with colorectal cancer in a first return of results visit, and findings not associated with colorectal cancer (incidental findings) during a second return of results visit. The primary outcome is efficacy to detect mutations associated with these syndromes; secondary outcomes include psychosocial impact, cost-effectiveness and comparative costs. The secondary outcomes will be obtained via surveys before and after each return visit. The expected challenges in conducting this randomized controlled trial include the relatively low prevalence of genetic disease, difficult interpretation of some genetic variants, and uncertainty about which incidental findings should be returned to patients. The approaches utilized in this study may help guide other investigators in clinical genomics to identify useful outcome measures and strategies to address comparative effectiveness questions about the clinical implementation of genomic sequencing in clinical care.

Published
2014

8. Allelic sequence diversity at the human β-globin locus

Author

Stephanie Malia. Fullerton

Subjects
Genetics, Sequence analysis, Genetic variation, Nucleic acid sequence, Allelic heterogeneity, Locus (genetics), Gene conversion, Human genetic variation, Biology, Gene
Abstract

The investigation of genetic variation at the DMA sequence level in Drosophila has demonstrated the success of the approach for elucidating the impact of molecular, selective, and demographic evolutionary processes. However, sequence level investigation of human genetic variation has thus far been limited to a single locus, the mitochondrial DNA genome. In order to extend the analysis of DNA sequence variation to human nuclear loci, and thereby bring the power of sequence analysis to the investigation of human population origins and affinities, allelic sequence diversity at the human β-globin gene was determined. A 3 kilobase (kb) genomic region, encompassing the human β-globin gene and associated flanking DNA, was examined. DNA sequence variation in this region was identified by direct sequence analysis of alleie-specific PCR amplification products. In total, 173 chromosomes from five human populations from Melanesia, Indonesia, and Africa, were investigated. Thirty-four polymorphisms were identified: 26 silent nucleotide differences, 2 non-silent (β haemoglobinopathies) variants, and 6 small insertion/deletion polymorphisms. These 34 polymorphisms were inherited as 53 different alleles, each defined by a unique sequence haplotype. Only 10 alleles were identified when the same genomic region was investigated by restriction enzyme analysis. The allelic sequence diversity identified suggested much about the influence of molecular, selective, and demographic phenomena. The unexpectedly high level of sequence haplotype polymorphism was found to be consistent with the pronounced impact of interallelic recombination in sequences 5' of the β-globin gene. Despite the presence of selected β haemoglobinopathies in some of the populations investigated, neither the genomic distribution nor the frequency of silent polymorphic sites was found to be inconsistent with that expected of a neutrally-evolving locus. Geographic differences in β-globin diversity were therefore attributed to the effects of mutation in partially subdivided populations as well as in specific cases reduction in population size and gene flow, rather than the influence of natural selection, and evaluated with respect to currently debated hypotheses concerning human evolutionary origins. The investigation of DNA sequence variation at the human β-globin locus has therefore contributed new insights into the evolution of the locus in human populations and provided an important new class of data with which to test hypotheses concerning the genetic origin of Homo sapiens sapiens .

Published
1996
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11. Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

Author

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

Subjects
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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