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1. Slice Testing—Considerations from Ordering to Reporting

Author

SoRelle, Jeffrey A., primary, Funke, Birgit H., additional, Eno, Celeste C., additional, Ji, Jianling, additional, Santani, Avni, additional, Bayrak-Toydemir, Pinar, additional, Wachsmann, Megan, additional, Wain, Karen E., additional, and Mao, Rong, additional

Published
2024
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6. Molecular Diagnostic Outcomes from 700 Cases

Author

Jill R. Murrell, Addie May I. Nesbitt, Samuel W. Baker, Kieran B. Pechter, Jorune Balciuniene, Xiaonan Zhao, Elizabeth H. Denenberg, Elizabeth T. DeChene, Chao Wu, Pushkala Jayaraman, Kajia Cao, Michael Gonzalez, Marcella Devoto, Alessandro Testori, John D. Monos, Matthew C. Dulik, Laura K. Conlin, Minjie Luo, Kristin McDonald Gibson, Qiaoning Guan, Mahdi Sarmady, Elizabeth Bhoj, Ingo Helbig, Elaine H. Zackai, Emma C. Bedoukian, Alisha Wilkens, Jennifer Tarpinian, Kosuke Izumi, Cara M. Skraban, Matthew A. Deardorff, Livija Medne, Ian D. Krantz, Bryan L. Krock, and Avni B. Santani

Subjects
Molecular Medicine, Pathology and Forensic Medicine
Published
2022

7. A Framework of Critical Considerations in Clinical Exome Reanalyses by Clinical and Laboratory Standards Institute

Author

Marco L. Leung, Jianling Ji, Samuel Baker, Jillian G. Buchan, Theru A. Sivakumaran, Bryan L. Krock, Rebecca Hutchins, Pinar Bayrak-Toydemir, John Pfeifer, Maria Laura Cremona, Birgit Funke, and Avni B. Santani

Subjects
Exome Sequencing, Humans, Molecular Medicine, Exome, Clinical Laboratory Services, Laboratories, Laboratories, Clinical, Pathology and Forensic Medicine
Abstract

Exome reanalysis is useful for providing molecular diagnoses for previously uninformative samples. However, challenges exist in implementing a practical solution for clinicians and laboratories. This study complements the current literature by providing practical considerations for patient-level and cohort-level reanalyses. The Clinical and Laboratory Standards Institute assembled the Document Development Committee and an interpretation working group that developed the framework for reevaluation of exome-based data. We describe two distinct but complementary approaches toward exome reanalyses: clinician-initiated patient-level reanalysis, and laboratory-initiated cohort-level reanalysis. We highlight the advantages and constraints for both approaches, and provide a high-level conceptual guide for ordering clinicians and laboratories through the critical decision pathways. Because clinical exome sequencing continues to be the standard of care in genetics, exome reanalysis would be critical in increasing the overall diagnostic yield. A systematic guide will facilitate the efficient adoption of reevaluation of exome data for laboratories, health care professionals, genetic counselors, and clinicians.

Published
2022

8. Neptune: an environment for the delivery of genomic medicine

Author

Venner Eric, Victoria Yi, David Murdock, Sara E. Kalla, Tsung-Jung Wu, Aniko Sabo, Shoudong Li, Qingchang Meng, Xia Tian, Mullai Murugan, Michelle Cohen, Christie Kovar, Wei-Qi Wei, Wendy K. Chung, Chunhua Weng, Georgia L. Wiesner, Gail P. Jarvik, Donna Muzny, Richard A. Gibbs, Debra Abrams, Samuel E. Adunyah, Ladia Albertson-Junkans, Berta Almoguera, Darren C. Ames, Paul Appelbaum, Samuel Aronson, Sharon Aufox, Lawrence J. Babb, Adithya Balasubramanian, Hana Bangash, Melissa Basford, Lisa Bastarache, Samantha Baxter, Meckenzie Behr, Barbara Benoit, Elizabeth Bhoj, Suzette J. Bielinski, Sarah T. Bland, Carrie Blout, Kenneth Borthwick, Erwin P. Bottinger, Mark Bowser, Harrison Brand, Murray Brilliant, Wendy Brodeur, Pedro Caraballo, David Carrell, Andrew Carroll, Lisa Castillo, Victor Castro, Gauthami Chandanavelli, Theodore Chiang, Rex L. Chisholm, Kurt D. Christensen, Wendy Chung, Christopher G. Chute, Brittany City, Beth L. Cobb, John J. Connolly, Paul Crane, Katherine Crew, David R. Crosslin, Jyoti Dayal, Mariza De Andrade, Jessica De la Cruz, Josh C. Denny, Shawn Denson, Tim DeSmet, Ozan Dikilitas, Michael J. Dinsmore, Sheila Dodge, Phil Dunlea, Todd L. Edwards, Christine M. Eng, David Fasel, Alex Fedotov, Qiping Feng, Mark Fleharty, Andrea Foster, Robert Freimuth, Christopher Friedrich, Stephanie M. Fullerton, Birgit Funke, Stacey Gabriel, Vivian Gainer, Ali Gharavi, Andrew M. Glazer, Joseph T. Glessner, Jessica Goehringer, Adam S. Gordon, Chet Graham, Robert C. Green, Justin H. Gundelach, Heather S. Hain, Hakon Hakonarson, Maegan V. Harden, John Harley, Margaret Harr, Andrea Hartzler, M. Geoffrey Hayes, Scott Hebbring, Nora Henrikson, Andrew Hershey, Christin Hoell, Ingrid Holm, Kayla M. Howell, George Hripcsak, Jianhong Hu, Elizabeth Duffy Hynes, Joy C. Jayaseelan, Yunyun Jiang, Yoonjung Yoonie Joo, Sheethal Jose, Navya Shilpa Josyula, Anne E. Justice, Divya Kalra, Elizabeth W. Karlson, Brendan J. Keating, Melissa A. Kelly, Eimear E. Kenny, Dustin Key, Krzysztof Kiryluk, Terrie Kitchner, Barbara Klanderman, Eric Klee, David C. Kochan, Viktoriya Korchina, Leah Kottyan, Emily Kudalkar, Alanna Kulchak Rahm, Iftikhar J. Kullo, Philip Lammers, Eric B. Larson, Matthew S. Lebo, Magalie Leduc, Ming Ta (Michael) Lee, Niall J. Lennon, Kathleen A. Leppig, Nancy D. Leslie, Rongling Li, Wayne H. Liang, Chiao-Feng Lin, Jodell E. Linder, Noralane M. Lindor, Todd Lingren, James G. Linneman, Cong Liu, Wen Liu, Xiuping Liu, John Lynch, Hayley Lyon, Alyssa Macbeth, Harshad Mahadeshwar, Lisa Mahanta, Bradley Malin, Teri Manolio, Maddalena Marasa, Keith Marsolo, Michelle L. McGowan, Elizabeth McNally, Jim Meldrim, Frank Mentch, Hila Milo Rasouly, Jonathan Mosley, Shubhabrata Mukherjee, Thomas E. Mullen, Jesse Muniz, David R. Murdock, Shawn Murphy, Melanie F. Myers, Bahram Namjou, Yizhao Ni, Robert C. Onofrio, Aniwaa Owusu Obeng, Thomas N. Person, Josh F. Peterson, Lynn Petukhova, Cassandra J. Pisieczko, Siddharth Pratap, Cynthia A. Prows, Megan J. Puckelwartz, Ritika Raj, James D. Ralston, Arvind Ramaprasan, Andrea Ramirez, Luke Rasmussen, Laura Rasmussen-Torvik, Soumya Raychaudhuri, Heidi L. Rehm, Marylyn D. Ritchie, Catherine Rives, Beenish Riza, Dan M. Roden, Elisabeth A. Rosenthal, Avni Santani, Schaid Dan, Steven Scherer, Stuart Scott, Aaron Scrol, Soumitra Sengupta, Ning Shang, Himanshu Sharma, Richard R. Sharp, Rajbir Singh, Patrick M.A. Sleiman, Kara Slowik, Joshua C. Smith, Maureen E. Smith, Duane T. Smoot, Jordan W. Smoller, Sunghwan Sohn, Ian B. Stanaway, Justin Starren, Mary Stroud, Jessica Su, Casey Overby Taylor, Kasia Tolwinski, Sara L. Van Driest, Sean M. Vargas, Matthew Varugheese, David Veenstra, Eric Venner, Miguel Verbitsky, Gina Vicente, Michael Wagner, Kimberly Walker, Theresa Walunas, Liwen Wang, Qiaoyan Wang, Scott T. Weiss, Quinn S. Wells, Peter S. White, Ken L. Wiley, Janet L. Williams, Marc S. Williams, Michael W. Wilson, Leora Witkowski, Laura Allison Woods, Betty Woolf, Julia Wynn, Yaping Yang, Ge Zhang, Lan Zhang, and Hana Zouk

Subjects
Computer science, business.industry, Process (engineering), MEDLINE, High-Throughput Nucleotide Sequencing, Genomics, Data science, Article, Personalization, Variety (cybernetics), Workflow, Neptune, Pharmacogenomics, Health care, Electronic Health Records, Humans, business, Software, Genetics (clinical)
Abstract

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Published
2021

9. Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation

Author

Ana Berta Sousa, Anneke J.A. Kievit, Marjon van Slegtenhorst, Nicholas J. Hand, Kosuke Izumi, Paula Jorge, Andrew C. Edmondson, Elisa De Franco, Linlea Armstrong, Michael E. March, Dirk Lefeber, Hans van Bokhoven, Miao He, Sian Ellard, Marina P Hommersom, Serwet Demirdas, Elaine H. Zackai, Fleur S van Dijk, Anna Lehman, Avni Santani, Daniel L. Polla, Daniel J. Rader, Arjan P.M. de Brouwer, Sandrine Duvet, Xin Bi, Sophie C. Huffels, Dmitriy Niyazov, Céline Schulz, Clinical Genetics, and Repositório da Universidade de Lisboa

Subjects
Male, Glycosylation, Mouse, Developmental Disabilities, Endoplasmic Reticulum, Compound heterozygosity, chemistry.chemical_compound, Congenital Disorders of Glycosylation, 0302 clinical medicine, EIF2AK3, Child, Genetics (clinical), Exome sequencing, 0303 health sciences, Tunicamycin, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Pedigree, Mannosidase, Child, Preschool, N-glycan, Female, Adolescent, Biology, Cell Line, 03 medical and health sciences, Polysaccharides, alpha-Mannosidase, Intellectual Disability, Report, Genetics, medicine, Humans, Proteostasis Deficiencies, Gene, Alleles, Glycoproteins, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Endoplasmic reticulum, Calcium-Binding Proteins, Infant, medicine.disease, Molecular biology, carbohydrates (lipids), Dysmorphism, chemistry, Mutation, Unfolded protein response, High-mannose, CDG, EDEM3, Congenital disorder of glycosylation, 030217 neurology & neurosurgery
Abstract

© 2021 American Society of Human Genetics, EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG., This work was supported by the EU FP7 large-scale integrating project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.); National Institutes of Health (NIH) grants 5R01GM115730-03 (to M.H.), U54 NS115198 (to A.C.E. and M.H.), and T32GM008638 (to A.C.E.); and the Transatlantic Network of Excellence grant (10CVD03) from the Fondation Leducq and NIH NHGRI U01HG006398 (to D.J.R.). Family 4 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). X.B. is supported by an AHA career development award (19CDA34630032).

Published
2021

10. Molecular Diagnostic Outcomes from 700 Cases

Author

Murrell, Jill R., primary, Nesbitt, Addie May I., additional, Baker, Samuel W., additional, Pechter, Kieran B., additional, Balciuniene, Jorune, additional, Zhao, Xiaonan, additional, Denenberg, Elizabeth H., additional, DeChene, Elizabeth T., additional, Wu, Chao, additional, Jayaraman, Pushkala, additional, Cao, Kajia, additional, Gonzalez, Michael, additional, Devoto, Marcella, additional, Testori, Alessandro, additional, Monos, John D., additional, Dulik, Matthew C., additional, Conlin, Laura K., additional, Luo, Minjie, additional, McDonald Gibson, Kristin, additional, Guan, Qiaoning, additional, Sarmady, Mahdi, additional, Bhoj, Elizabeth, additional, Helbig, Ingo, additional, Zackai, Elaine H., additional, Bedoukian, Emma C., additional, Wilkens, Alisha, additional, Tarpinian, Jennifer, additional, Izumi, Kosuke, additional, Skraban, Cara M., additional, Deardorff, Matthew A., additional, Medne, Livija, additional, Krantz, Ian D., additional, Krock, Bryan L., additional, and Santani, Avni B., additional

Published
2022
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12. A Framework of Critical Considerations in Clinical Exome Reanalyses by Clinical and Laboratory Standards Institute

Author

Leung, Marco L., primary, Ji, Jianling, additional, Baker, Samuel, additional, Buchan, Jillian G., additional, Sivakumaran, Theru A., additional, Krock, Bryan L., additional, Hutchins, Rebecca, additional, Bayrak-Toydemir, Pinar, additional, Pfeifer, John, additional, Cremona, Maria Laura, additional, Funke, Birgit, additional, and Santani, Avni B., additional

Published
2022
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13. Clinical utility of exome sequencing in infantile heart failure

Author

Alyssa Ritter, Christopher Gray, Ian D. Krantz, Sandra Yang, Livija Medne, Avni Santani, Cara M. Skraban, Kosuke Izumi, Deborah Copenheaver, Jane Juusola, Rebecca C. Ahrens-Nicklas, Emma Bedoukian, Kimberly Y. Lin, Jacqueline Leonard, and Justin H Berger

Subjects
Cardiomyopathy, Dilated, Male, Pediatrics, medicine.medical_specialty, Cardiomyopathy, Article, Intensive care, Exome Sequencing, medicine, Humans, Exome, Genetic Testing, Medical diagnosis, Genetics (clinical), Exome sequencing, Genetic testing, Heart Failure, medicine.diagnostic_test, business.industry, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Dilated cardiomyopathy, medicine.disease, Treatment Outcome, Heart failure, Female, Differential diagnosis, Cardiomyopathies, business
Abstract

PURPOSE: Pediatric cardiomyopathy is rare, has a broad differential diagnosis, results in high morbidity and mortality, and has sub-optimal diagnostic yield using next generation sequencing panels. Exome sequencing has reported diagnostic yields ranging from 30-57% for neonates in intensive care units. We aimed to characterize the clinical utility of exome sequencing in infantile heart failure. METHODS: Infants diagnosed with acute heart failure prior to 1 year old over a period of 34 months at a large tertiary children’s hospital were recruited. Demographic and diagnostic information was obtained from medical records. Fifteen eligible patients were enrolled. RESULTS: Dilated cardiomyopathy was the predominant cardiac diagnosis, seen in 60% of patients. Molecular diagnosis was identified in 66.7% of patients (10/15). Of those diagnoses, 70% would not have been detected using multi-gene next generation sequencing panels focused on cardiomyopathy or arrhythmia disease genes. Genetic testing changed medical decision-making in 53% of all cases and 80% of positive cases, and was especially beneficial when testing was expedited. CONCLUSIONS: Given the broad differential diagnosis and critical status of infants with heart failure, rapid exome sequencing provides timely diagnoses, changes medical management, and should be the first-tier molecular test.

Published
2020

14. Neptune: an environment for the delivery of genomic medicine

Author

Eric, Venner, primary, Yi, Victoria, additional, Murdock, David, additional, Kalla, Sara E., additional, Wu, Tsung-Jung, additional, Sabo, Aniko, additional, Li, Shoudong, additional, Meng, Qingchang, additional, Tian, Xia, additional, Murugan, Mullai, additional, Cohen, Michelle, additional, Kovar, Christie, additional, Wei, Wei-Qi, additional, Chung, Wendy K., additional, Weng, Chunhua, additional, Wiesner, Georgia L., additional, Jarvik, Gail P., additional, Muzny, Donna, additional, Gibbs, Richard A., additional, Abrams, Debra, additional, Adunyah, Samuel E., additional, Albertson-Junkans, Ladia, additional, Almoguera, Berta, additional, Ames, Darren C., additional, Appelbaum, Paul, additional, Aronson, Samuel, additional, Aufox, Sharon, additional, Babb, Lawrence J., additional, Balasubramanian, Adithya, additional, Bangash, Hana, additional, Basford, Melissa, additional, Bastarache, Lisa, additional, Baxter, Samantha, additional, Behr, Meckenzie, additional, Benoit, Barbara, additional, Bhoj, Elizabeth, additional, Bielinski, Suzette J., additional, Bland, Sarah T., additional, Blout, Carrie, additional, Borthwick, Kenneth, additional, Bottinger, Erwin P., additional, Bowser, Mark, additional, Brand, Harrison, additional, Brilliant, Murray, additional, Brodeur, Wendy, additional, Caraballo, Pedro, additional, Carrell, David, additional, Carroll, Andrew, additional, Castillo, Lisa, additional, Castro, Victor, additional, Chandanavelli, Gauthami, additional, Chiang, Theodore, additional, Chisholm, Rex L., additional, Christensen, Kurt D., additional, Chung, Wendy, additional, Chute, Christopher G., additional, City, Brittany, additional, Cobb, Beth L., additional, Connolly, John J., additional, Crane, Paul, additional, Crew, Katherine, additional, Crosslin, David R., additional, Dayal, Jyoti, additional, De Andrade, Mariza, additional, De la Cruz, Jessica, additional, Denny, Josh C., additional, Denson, Shawn, additional, DeSmet, Tim, additional, Dikilitas, Ozan, additional, Dinsmore, Michael J., additional, Dodge, Sheila, additional, Dunlea, Phil, additional, Edwards, Todd L., additional, Eng, Christine M., additional, Fasel, David, additional, Fedotov, Alex, additional, Feng, Qiping, additional, Fleharty, Mark, additional, Foster, Andrea, additional, Freimuth, Robert, additional, Friedrich, Christopher, additional, Fullerton, Stephanie M., additional, Funke, Birgit, additional, Gabriel, Stacey, additional, Gainer, Vivian, additional, Gharavi, Ali, additional, Glazer, Andrew M., additional, Glessner, Joseph T., additional, Goehringer, Jessica, additional, Gordon, Adam S., additional, Graham, Chet, additional, Green, Robert C., additional, Gundelach, Justin H., additional, Hain, Heather S., additional, Hakonarson, Hakon, additional, Harden, Maegan V., additional, Harley, John, additional, Harr, Margaret, additional, Hartzler, Andrea, additional, Hayes, M. Geoffrey, additional, Hebbring, Scott, additional, Henrikson, Nora, additional, Hershey, Andrew, additional, Hoell, Christin, additional, Holm, Ingrid, additional, Howell, Kayla M., additional, Hripcsak, George, additional, Hu, Jianhong, additional, Hynes, Elizabeth Duffy, additional, Jayaseelan, Joy C., additional, Jiang, Yunyun, additional, Joo, Yoonjung Yoonie, additional, Jose, Sheethal, additional, Josyula, Navya Shilpa, additional, Justice, Anne E., additional, Kalra, Divya, additional, Karlson, Elizabeth W., additional, Keating, Brendan J., additional, Kelly, Melissa A., additional, Kenny, Eimear E., additional, Key, Dustin, additional, Kiryluk, Krzysztof, additional, Kitchner, Terrie, additional, Klanderman, Barbara, additional, Klee, Eric, additional, Kochan, David C., additional, Korchina, Viktoriya, additional, Kottyan, Leah, additional, Kudalkar, Emily, additional, Rahm, Alanna Kulchak, additional, Kullo, Iftikhar J., additional, Lammers, Philip, additional, Larson, Eric B., additional, Lebo, Matthew S., additional, Leduc, Magalie, additional, Lee, Ming Ta (Michael), additional, Lennon, Niall J., additional, Leppig, Kathleen A., additional, Leslie, Nancy D., additional, Li, Rongling, additional, Liang, Wayne H., additional, Lin, Chiao-Feng, additional, Linder, Jodell E., additional, Lindor, Noralane M., additional, Lingren, Todd, additional, Linneman, James G., additional, Liu, Cong, additional, Liu, Wen, additional, Liu, Xiuping, additional, Lynch, John, additional, Lyon, Hayley, additional, Macbeth, Alyssa, additional, Mahadeshwar, Harshad, additional, Mahanta, Lisa, additional, Malin, Bradley, additional, Manolio, Teri, additional, Marasa, Maddalena, additional, Marsolo, Keith, additional, McGowan, Michelle L., additional, McNally, Elizabeth, additional, Meldrim, Jim, additional, Mentch, Frank, additional, Rasouly, Hila Milo, additional, Mosley, Jonathan, additional, Mukherjee, Shubhabrata, additional, Mullen, Thomas E., additional, Muniz, Jesse, additional, Murdock, David R., additional, Murphy, Shawn, additional, Myers, Melanie F., additional, Namjou, Bahram, additional, Ni, Yizhao, additional, Onofrio, Robert C., additional, Obeng, Aniwaa Owusu, additional, Person, Thomas N., additional, Peterson, Josh F., additional, Petukhova, Lynn, additional, Pisieczko, Cassandra J., additional, Pratap, Siddharth, additional, Prows, Cynthia A., additional, Puckelwartz, Megan J., additional, Raj, Ritika, additional, Ralston, James D., additional, Ramaprasan, Arvind, additional, Ramirez, Andrea, additional, Rasmussen, Luke, additional, Rasmussen-Torvik, Laura, additional, Raychaudhuri, Soumya, additional, Rehm, Heidi L., additional, Ritchie, Marylyn D., additional, Rives, Catherine, additional, Riza, Beenish, additional, Roden, Dan M., additional, Rosenthal, Elisabeth A., additional, Santani, Avni, additional, Dan, Schaid, additional, Scherer, Steven, additional, Scott, Stuart, additional, Scrol, Aaron, additional, Sengupta, Soumitra, additional, Shang, Ning, additional, Sharma, Himanshu, additional, Sharp, Richard R., additional, Singh, Rajbir, additional, Sleiman, Patrick M.A., additional, Slowik, Kara, additional, Smith, Joshua C., additional, Smith, Maureen E., additional, Smoot, Duane T., additional, Smoller, Jordan W., additional, Sohn, Sunghwan, additional, Stanaway, Ian B., additional, Starren, Justin, additional, Stroud, Mary, additional, Su, Jessica, additional, Taylor, Casey Overby, additional, Tolwinski, Kasia, additional, Van Driest, Sara L., additional, Vargas, Sean M., additional, Varugheese, Matthew, additional, Veenstra, David, additional, Venner, Eric, additional, Verbitsky, Miguel, additional, Vicente, Gina, additional, Wagner, Michael, additional, Walker, Kimberly, additional, Walunas, Theresa, additional, Wang, Liwen, additional, Wang, Qiaoyan, additional, Weiss, Scott T., additional, Wells, Quinn S., additional, White, Peter S., additional, Wiley, Ken L., additional, Williams, Janet L., additional, Williams, Marc S., additional, Wilson, Michael W., additional, Witkowski, Leora, additional, Woods, Laura Allison, additional, Woolf, Betty, additional, Wynn, Julia, additional, Yang, Yaping, additional, Zhang, Ge, additional, Zhang, Lan, additional, and Zouk, Hana, additional

Published
2021
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15. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network

Author

Ian B. Stanaway, Dan M. Roden, Divya Kalra, Dustin Key, Debra J. Abrams, David Fasel, Victor Castro, Brad Malin, Berta Almoguera, Beenish Riza, Meckenzie A. Behr, Eric Venner, Christine M. Eng, Joy Jayaseelan, Scott J. Hebbring, Michelle L. McGowan, Steven E. Scherer, Theresa L. Walunas, Mark Bowser, James D. Ralston, Wei-Qi Wei, Liwen Wang, David R. Murdock, Wayne H. Liang, Julia Wynn, Nancy D. Leslie, Laura J. Rasmussen-Torvik, Ming Ta (Michael) Lee, Frank D. Mentch, Lan Zhang, Alanna Kulchak Rahm, Josh F. Peterson, Jodell E. Linder, Joshua C. Smith, Soumitra Sengupta, Brendan J. Keating, Gina Vicente, Andrew Carroll, Nora B. Henrikson, Anne E. Justice, Heather S. Hain, Wen Liu, Andrea H. Ramirez, Matthew S. Lebo, Hana Zouk, Georgia L. Wiesner, Andrea L. Hartzler, Cassandra J. Pisieczko, Catherine M. Rives, Jessica Goehringer, Maegan V. Harden, John Lynch, Chiao-Feng Lin, Peter White, Phil Dunlea, Shawn N. Murphy, Mullai Murugan, Harshad Mahadeshwar, Mark Fleharty, Andrea Foster, Arvind Ramaprasan, Christopher A. Friedrich, Justin H. Gundelach, Hayley Lyon, Niall J. Lennon, Eric W. Klee, David R. Crosslin, Ge Zhang, Rongling Li, Ozan Dikilitas, Xiuping Liu, Christin Hoell, Aniwaa Owusu Obeng, Katherine D. Crew, Lisa M. Castillo, Justin Starren, Jonathan D. Mosley, Carrie L. Blout, Himanshu Sharma, Elizabeth M. McNally, Sarah T. Bland, Megan J. Puckelwartz, Matthew Varugheese, Keith Marsolo, Betty Woolf, Sharon Aufox, Janet L. Williams, Kimberly Walker, Murray H. Brilliant, Birgit Funke, Laura Allison Woods, Marylyn D. Ritchie, Brittany City, Todd Lingren, Hila Milo Rasouly, Lawrence J. Babb, Alex Fedotov, Robert C. Onofrio, Margaret Harr, Suzette J. Bielinski, Michael W. Wilson, Shubhabrata Mukherjee, Robert R. Freimuth, Chet Graham, Todd L. Edwards, Quinn S. Wells, Marc S. Williams, Jordan W. Smoller, Wendy K. Chung, Avni Santani, Paul K. Crane, George Hripcsak, QiPing Feng, Ali G. Gharavi, Yizhao Ni, Iftikhar J. Kullo, Michael Wagner, Philip E. Lammers, Michael J. Dinsmore, Thomas N. Person, Victoria Yi, Samuel E. Adunyah, Tim DeSmet, Eric B. Larson, Elizabeth Hynes, David C. Kochan, Eimear E. Kenny, Magalie S. Leduc, Lisa Mahanta, David Carrell, Paul S. Appelbaum, Viktoriya Korchina, Beth L. Cobb, Lynn Petukhova, Jessica De la Cruz, Patrick M. A. Sleiman, Stuart A. Scott, Tsung-Jung Wu, Gail P. Jarvik, Erwin P. Bottinger, Ken Wiley, Josh C. Denny, Melissa A. Basford, Samuel J. Aronson, David L. Veenstra, Yaping Yang, Kayla Marie Howell, John J. Connolly, Jessica Su, Yoonjung Yoonie Joo, Miguel Verbitsky, Sean M. Vargas, Cong Liu, Barbara Benoit, Andrew Hershey, Richard A. Gibbs, Cynthia A. Prows, Hana Bangash, Wendy Brodeur, Gauthami Chandanavelli, Sara L. Van Driest, Kurt D. Christensen, Elizabeth J. Bhoj, Vivian S. Gainer, Adam S. Gordon, Robert C. Green, Hakon Hakonarson, Krzysztof Kiryluk, Elisabeth A. Rosenthal, Rajbir Singh, James G. Linneman, Harrison Brand, Theodore Chiang, Sheila Dodge, Ingrid A. Holm, M. Geoffrey Hayes, Yunyun Jiang, Ning Shang, Samantha Baxter, Noralane M. Lindor, Kathleen A. Leppig, Teri A. Manolio, Sara E. Kalla, Pedro J. Caraballo, Ritika Raj, Aaron Scrol, Jyoti G. Dayal, Richard R. Sharp, Christie Kovar, Soumya Raychaudhuri, Sunghwan Sohn, Emily Kudalkar, Maddalena Marasa, Stacey Gabriel, Dan Schaid, Ladia Albertson-Junkans, Rex L. Chisholm, Maureen E. Smith, Donna M. Muzny, Casey Overby Taylor, Jianhong Hu, Elizabeth W. Karlson, Lisa Bastarache, Darren C. Ames, Joseph T. Glessner, Leora Witkowski, Siddharth Pratap, Qiaoyan Wang, Melissa A. Kelly, Adithya Balasubramanian, Kara Slowik, Terrie Kitchner, Barbara J. Klanderman, Shawn Denson, Mary Stroud, Alyssa Macbeth, Melanie F. Myers, Jesse Muniz, Kasia Tolwinski, Scott T. Weiss, Chunhua Weng, Stephanie M. Fullerton, John B. Harley, Christopher G. Chute, Heidi L. Rehm, Sheethal Jose, Andrew M. Glazer, Navya Shilpa Josyula, Kenneth M. Borthwick, Thomas E. Mullen, Mariza de Andrade, Leah C. Kottyan, Luke V. Rasmussen, James Meldrim, and Bahram Namjou

Subjects
0301 basic medicine, Standardization, Test data generation, business.industry, Computer science, Sequence Analysis, DNA, 030105 genetics & heredity, Precision medicine, Data science, Clinical decision support system, Biobank, Article, 3. Good health, Data sharing, 03 medical and health sciences, 030104 developmental biology, Genetics, Humans, Genetic Testing, Prospective Studies, Sample collection, Personalized medicine, Precision Medicine, business, Genetics (clinical)
Abstract

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

Published
2019

16. Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss

Author

Xiahoan Ying, Ariella Sasson, Matthew C. Dulik, Alisha Wilkens, Mahdi Sarmady, Batsal Devkota, Ramakrishnan Rajagopalan, Elizabeth T. DeChene, Minjie Luo, Ian D. Krantz, Jeffrey W. Pennington, Jenica L. Abrudan, Vijayakumar Jayaraman, Mindy H. Li, Edward J. Romasko, Laura K. Conlin, Sarah E Sheppard, Maria I. Scarano, Joshua Brunton, Avni Santani, Sowmya Jairam, Sarah E. Raible, Nancy B. Spinner, Sawona Biswas, Jiwon Choi, and Ian Slack

Subjects
Exome sequencing, Male, 0301 basic medicine, Proband, Oncology, medicine.medical_specialty, Hearing loss, Genetic diagnostics, Read depth, Sensorineural, 030105 genetics & heredity, Article, 03 medical and health sciences, Data sequences, Internal medicine, medicine, Humans, Exome, Pathology, Molecular, Medical diagnosis, Prospective cohort study, Genetics (clinical), business.industry, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, 3. Good health, Phenotype, 030104 developmental biology, Child, Preschool, Mutation, Female, medicine.symptom, business
Abstract

Purpose Hearing loss (HL) is the most common sensory disorder in children. Prompt molecular diagnosis may guide screening and management; especially in syndromic cases when HL is the single presenting feature. Exome sequencing (ES)is an appealing diagnostic tool for HL as the genetic causes are highly heterogeneous. Methods ES was performed on a prospective cohort of 43 probands with HL. Sequence data were analyzed for primary and secondary findings. Capture and coverage analysis was performed for genes and variants associated with HL. Results The diagnostic rate using ES was 37.2% compared to 15.8% with clinical HL panel. Secondary findings were discovered in three patients. For 247 genes associated with HL, 94.7% of the exons were targeted for capture and 81.7% of these exons were covered at 20× or greater. Further analysis of 454 randomly selected HL-associated variants showed 89% were targeted for capture and 75% were covered at a read depth of at least 20×. Conclusion ES has an improved yield to clinical testing and may capture diagnoses not initially considered due to subtle clinical phenotypes. Technical challenges were identified, including inadequate capture and coverage of HL genes. Additional considerations of ES include secondary findings, cost, and turnaround time.

Published
2018

17. Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation

Author

Polla, Daniel L., primary, Edmondson, Andrew C., additional, Duvet, Sandrine, additional, March, Michael E., additional, Sousa, Ana Berta, additional, Lehman, Anna, additional, Niyazov, Dmitriy, additional, van Dijk, Fleur, additional, Demirdas, Serwet, additional, van Slegtenhorst, Marjon A., additional, Kievit, Anneke J.A., additional, Schulz, Celine, additional, Armstrong, Linlea, additional, Bi, Xin, additional, Rader, Daniel J., additional, Izumi, Kosuke, additional, Zackai, Elaine H., additional, de Franco, Elisa, additional, Jorge, Paula, additional, Huffels, Sophie C., additional, Hommersom, Marina, additional, Ellard, Sian, additional, Lefeber, Dirk J., additional, Santani, Avni, additional, Hand, Nicholas J., additional, van Bokhoven, Hans, additional, He, Miao, additional, and de Brouwer, Arjan P.M., additional

Published
2021
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19. Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers

Author

David E. Gray, Michael O. Dorschner, Matthew S. Lebo, Nikhil Wagle, Ellen A. Tsai, Avni Santani, Heidi L. Rehm, Sean McGee, Mahdi Sarmady, Andrew Dunford, Celine S. Hong, Levi A. Garraway, Kimberly Walker, Deborah A. Nickerson, Carrie Cibulskis, Joshua Sailsbery, David S. Hanna, Dan R. Robinson, Lucia A. Hindorff, Christian J. Buhay, Rashesh Sanghvi, Leslie G. Biesecker, Kevin M. Bowling, Ariella Sasson, Carolyn M. Hutter, Bradford C. Powell, Gregory M. Cooper, Christine Brennan, Donna M. Muzny, Mauricio O. Carneiro, and Robert J. Lonigro

Subjects
0301 basic medicine, Sequencing standards, Computer science, clinical sequencing, Computational biology, Bioinformatics, Genome, Article, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Humans, Exome, Road map, genome, Genetics (clinical), Exome sequencing, Whole genome sequencing, Massive parallel sequencing, Base Sequence, Whole Genome Sequencing, Genome, Human, Chromosome Mapping, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Human genome, Software
Abstract

PURPOSE: As massively parallel sequencing is increasingly being used for clinical decision-making, it has become critical to understand parameters that affect sequencing quality and to establish methods for measuring and reporting clinical sequencing standards. In this report, we propose a definition for reduced coverage regions and have established a set of standards for variant calling in clinical sequencing applications. METHODS: To enable sequencing centers to assess the regions of poor sequencing quality in their own data, we optimized and used a tool (ExCid) to identify reduced coverage loci within genes or regions of particular interest. We used this framework to examine sequencing data from 500 patients generated in ten projects from sequencing centers in the NHGRI/NCI Clinical Sequencing Exploratory Research (CSER) Consortium. RESULTS: This approach identified reduced coverage regions in clinically relevant genes, including known clinically relevant loci that were uniquely missed at individual centers, in multiple centers, and in all centers. CONCLUSIONS: This report provides a process roadmap for clinical sequencing centers looking to perform similar analyses on their data.

Published
2018

20. Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Author

Alisha Wilkens, Ian D. Krantz, Laura K. Conlin, Mahdi Sarmady, Nancy B. Spinner, Addie I. Nesbitt, Zhenming Yu, Elizabeth J. Bhoj, Eric D. Marsh, Dimitri S. Monos, Elizabeth Denenberg, Peter White, Chao Wu, Jeffrey W. Pennington, Xiangdong Zhou, Kajia Cao, Avni Santani, Matt Deardorff, Emma Bedoukian, Qiaoning Guan, Bo Zhang, Holly Dubbs, Elaine H. Zackai, Kristin McDonald Gibson, Elizabeth T. DeChene, Minjie Luo, and Livija Medne

Subjects
0301 basic medicine, Genomic data, Zhàng, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, Computational biology, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Validation testing, 03 medical and health sciences, INDEL Mutation, Data accuracy, Humans, Exome, Genetic Predisposition to Disease, Genetic Testing, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Genetic Association Studies, Genetics (clinical), Genetics, Interpretation (philosophy), Computational Biology, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Genomics, Sequence Analysis, DNA, Data Accuracy, 030104 developmental biology, ComputingMethodologies_GENERAL, Psychology
Abstract

PurposeThe objective of this study was to assess the ability of our laboratory's exome-sequencing test to detect known and novel sequence variants and identify the critical factors influencing the interpretation of a clinical exome test.MethodsWe developed a two-tiered validation strategy: (i) a method-based approach that assessed the ability of our exome test to detect known variants using a reference HapMap sample, and (ii) an interpretation-based approach that assessed our relative ability to identify and interpret disease-causing variants, by analyzing and comparing the results of 19 randomly selected patients previously tested by external laboratories.ResultsWe demonstrate that this approach is reproducible with99% analytical sensitivity and specificity for single-nucleotide variants and indels10 bp. Our findings were concordant with the reference laboratories in 84% of cases. A new molecular diagnosis was applied to three cases, including discovery of two novel candidate genes.ConclusionWe provide an assessment of critical areas that influence interpretation of an exome test, including comprehensive phenotype capture, assessment of clinical overlap, availability of parental data, and the addressing of limitations in database updates. These results can be used to inform improvements in phenotype-driven interpretation of medical exomes in clinical and research settings.

Published
2018

23. Correction: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author

Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, and Ping Yee Billie Au

Subjects
Genetics (clinical)
Published
2021

25. Correction: The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

Author

Weiss, Karin, primary, Lazar, Hayley P., additional, Kurolap, Alina, additional, Martinez, Ariel F., additional, Paperna, Tamar, additional, Cohen, Lior, additional, Smeland, Marie F., additional, Whalen, Sandra, additional, Heide, Solveig, additional, Keren, Boris, additional, Terhal, Pauline, additional, Irving, Melita, additional, Takaku, Motoki, additional, Roberts, John D., additional, Petrovich, Robert M., additional, Vergano, Samantha A. Schrier, additional, Kenney, Amy, additional, Hove, Hanne, additional, DeChene, Elizabeth, additional, Quinonez, Shane C., additional, Colin, Estelle, additional, Ziegler, Alban, additional, Rumple, Melissa, additional, Jain, Mahim, additional, Monteil, Danielle, additional, Roeder, Elizabeth R., additional, Nugent, Kimberly, additional, van Haeringen, Arie, additional, Gambello, Michael, additional, Santani, Avni, additional, Medne, Līvija, additional, Krock, Bryan, additional, Skraban, Cara M., additional, Zackai, Elaine H., additional, Dubbs, Holly A., additional, Smol, Thomas, additional, Ghoumid, Jamal, additional, Parker, Michael J., additional, Wright, Michael, additional, Turnpenny, Peter, additional, Clayton-Smith, Jill, additional, Metcalfe, Kay, additional, Kurumizaka, Hitoshi, additional, Gelb, Bruce D., additional, Feldman, Hagit Baris, additional, Campeau, Philippe M., additional, Muenke, Maximilian, additional, Wade, Paul A., additional, and Lachlan, Katherine, additional

Published
2020
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26. The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

Author

Weiss, Karin, primary, Lazar, Hayley P., additional, Kurolap, Alina, additional, Martinez, Ariel F., additional, Paperna, Tamar, additional, Cohen, Lior, additional, Smeland, Marie F., additional, Whalen, Sandra, additional, Heide, Solveig, additional, Keren, Boris, additional, Terhal, Pauline, additional, Irving, Melita, additional, Takaku, Motoki, additional, Roberts, John D., additional, Petrovich, Robert M., additional, Schrier Vergano, Samantha A., additional, Kenney, Amy, additional, Hove, Hanne, additional, DeChene, Elizabeth, additional, Quinonez, Shane C., additional, Colin, Estelle, additional, Ziegler, Alban, additional, Rumple, Melissa, additional, Jain, Mahim, additional, Monteil, Danielle, additional, Roeder, Elizabeth R., additional, Nugent, Kimberly, additional, van Haeringen, Arie, additional, Gambello, Michael, additional, Santani, Avni, additional, Medne, Līvija, additional, Krock, Bryan, additional, Skraban, Cara M., additional, Zackai, Elaine H., additional, Dubbs, Holly A., additional, Smol, Thomas, additional, Ghoumid, Jamal, additional, Parker, Michael J., additional, Wright, Michael, additional, Turnpenny, Peter, additional, Clayton-Smith, Jill, additional, Metcalfe, Kay, additional, Kurumizaka, Hitoshi, additional, Gelb, Bruce D., additional, Baris Feldman, Hagit, additional, Campeau, Philippe M., additional, Muenke, Maximilian, additional, Wade, Paul A., additional, and Lachlan, Katherine, additional

Published
2020
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27. Clinical utility of exome sequencing in infantile heart failure

Author

Ritter, Alyssa, primary, Bedoukian, Emma, additional, Berger, Justin H., additional, Copenheaver, Deborah, additional, Gray, Christopher, additional, Krantz, Ian, additional, Izumi, Kosuke, additional, Juusola, Jane, additional, Leonard, Jacqueline, additional, Lin, Kimberly, additional, Medne, Livija, additional, Santani, Avni, additional, Skraban, Cara, additional, Yang, Sandra, additional, and Ahrens-Nicklas, Rebecca C., additional

Published
2020
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28. WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

Author

Dagmar Wieczorek, Stephen P. Robertson, Lynne M. Bird, Megan T. Cho, Avni Santani, Amber Begtrup, Cara M. Skraban, Marlies Kempers, Richard E. Person, Tjitske Kleefstra, Martina M. Owens, Koen L.I. van Gassen, Kristin McDonald Gibson, Alice Goldenberg, Preetha Markose, Evelien Zonneveld-Huijssoon, Katelyn Payne, Arjan P.M. de Brouwer, Taylor C. Warner, Jane Juusola, Matthew A. Deardorff, Kajia Cao, John A. Bernat, Claire L. S. Turner, Addie I. Nesbitt, Esther Kinning, Amber Stocco, Patricia G. Wheeler, Nienke E. Verbeek, Alisha Wilkens, David Markie, Ganka Douglas, A. Micheil Innes, Elizabeth Denenberg, P.Y. Billie Au, Katheryn Grand, Rolph Pfundt, Constance F. Wells, and Laurence E. Walsh

Subjects
Male, 0301 basic medicine, RNA Stability, Haploinsufficiency, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Seizures, Report, Intellectual Disability, Intellectual disability, Journal Article, Genetics, Spastic, medicine, Humans, Missense mutation, Genetics(clinical), Amino Acid Sequence, Child, Preschool, Gait, Exome, Genetics (clinical), Adaptor Proteins, Signal Transducing, 1q41q42 microdeletion syndrome, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Facies, Proteins, Syndrome, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Female, Growth and Development, Chromosome Deletion, 030217 neurology & neurosurgery, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 177285.pdf (Publisher’s version ) (Closed access) We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in approximately 1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.

Published
2017

29. Phenotypic predictors and final diagnoses in patients referred for RASopathy testing by targeted next-generation sequencing

Author

Zhenming Yu, Matthew A. Deardorff, Avni Santani, Kajia Cao, Rebecca C. Ahrens-Nicklas, Minjie Luo, Tanya Tischler, Qiaoning Guan, Elizabeth J. Bhoj, and Elaine H. Zackai

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, MAP Kinase Signaling System, Physical examination, 030105 genetics & heredity, RASopathy, Negative Test Result, Article, 03 medical and health sciences, Costello syndrome, LEOPARD Syndrome, Humans, Medicine, Medical diagnosis, Genetics (clinical), Retrospective Studies, Genetic testing, medicine.diagnostic_test, business.industry, Costello Syndrome, Noonan Syndrome, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, 030104 developmental biology, ras Proteins, Noonan syndrome, Differential diagnosis, business
Abstract

RASopathies include disorders generally characterized by developmental delay, specific heart defects, short stature, cardiac hypertrophy, and facial dysmorphisms. Next-generation sequencing (NGS)-based panels have widespread acceptance as a diagnostic tool for RASopathies. The first 126 patients evaluated by clinical examination and the NGS RASopathy panel at the Children’s Hospital of Philadelphia were enrolled. We calculated diagnosis rate, correlated reported clinical findings with positive or negative test results, and identified final molecular diagnoses in 28/96 patients who tested negative for RASopathies. Twenty-four patients had pathogenic variants on the RASopathy panel, for a diagnostic yield of 19%. Reported features of pulmonic stenosis and ptosis were significantly correlated with a positive test result; no reported features were significantly correlated with a negative test result. We identified 27 different alternative diagnoses for patients originally suspected of having RASopathies. This study provides information that can assist in guiding differential diagnosis and genetic testing for patients suspected of having a RASopathy disorder. Genet Med advance online publication 20 October 2016

Published
2017

30. A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories

Author

Amy K. Johnson, Heidi L. Rehm, Madhuri Hegde, Kevin M. Bowling, C. Sue Richards, Wendy K. Chung, Gail P. Jarvik, Susan M. Wolf, Karen E. Weck, Michele C. Gornick, Joshua L. Deignan, Brian H. Shirts, James P. Evans, Soma Das, Sumit Punj, Lindsey Mighion, Sharon E. Plon, Massimo Morra, Julianne M. O’Daniel, Arezou A. Ghazani, Katrina A.B. Goddard, Sherri J. Bale, Tina Hambuch, Sha Tang, Gregory M. Cooper, Lucia A. Hindorff, Kelly D. Farwell Hagman, Ingrid A. Holm, Elizabeth C. Chao, Heather M. McLaughlin, Laura K. Conlin, Nancy B. Spinner, Avni Santani, David P. Bick, Yaping Yang, Jonathan S. Berg, Laura M. Amendola, and Michael O. Dorschner

Subjects
methods, standards [Sequence Analysis, DNA], Research Report, 0301 basic medicine, Best practice, Disclosure, 030105 genetics & heredity, Biology, Bioinformatics, Article, genetic testing, ethics, standards [Laboratories], 03 medical and health sciences, Documentation, laboratory standards, Surveys and Questionnaires, Medicine and Health Sciences, Humans, standards [Genetic Testing], clinical reporting, Exome, Genetics (clinical), Exome sequencing, Multiple choice, Incidental Findings, Medical education, Information Dissemination, Sequence Analysis, DNA, 3. Good health, genome sequencing, Data sharing, 030104 developmental biology, Workflow, Sample Size, Practice Guidelines as Topic, Laboratories, exome sequencing, Personal genomics
Abstract

While the diagnostic success of genomic sequencing expands, the complexity of this testing should not be overlooked. Numerous laboratory processes are required to support the identification, interpretation, and reporting of clinically significant variants. This study aimed to examine the workflow and reporting procedures among US laboratories to highlight shared practices and identify areas in need of standardization. Surveys and follow-up interviews were conducted with laboratories offering exome and/or genome sequencing to support a research program or for routine clinical services. The 73-item survey elicited multiple choice and free-text responses that were later clarified with phone interviews. Twenty-one laboratories participated. Practices highly concordant across all groups included consent documentation, multiperson case review, and enabling patient opt-out of incidental or secondary findings analysis. Noted divergence included use of phenotypic data to inform case analysis and interpretation and reporting of case-specific quality metrics and methods. Few laboratory policies detailed procedures for data reanalysis, data sharing, or patient access to data. This study provides an overview of practices and policies of experienced exome and genome sequencing laboratories. The results enable broader consideration of which practices are becoming standard approaches, where divergence remains, and areas of development in best practice guidelines that may be helpful.Genet Med advance online publication 03 Novemeber 2016.

Published
2017

31. Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing

Author

Matthew S. Lebo, Arunkanth Ankala, Mark Bowser, Ryan J. Schmidt, Avni Santani, Elizabeth Duffy, Birgit Funke, Diana Mandelker, Madhuri Hegde, Kristin McDonald Gibson, and Himanshu Sharma

Subjects
0301 basic medicine, Sequence analysis, Pseudogene, Computational biology, Homology (biology), DNA sequencing, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Humans, Medicine, Exome, Pathology, Molecular, Gene, Genetics (clinical), Exome sequencing, Homologous gene, Genetics, Sanger sequencing, business.industry, Computational Biology, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, symbols, business
Abstract

Next-generation sequencing (NGS) is now routinely used to interrogate large sets of genes in a diagnostic setting. Regions of high sequence homology continue to be a major challenge for short-read technologies and can lead to false-positive and false-negative diagnostic errors. At the scale of whole-exome sequencing (WES), laboratories may be limited in their knowledge of genes and regions that pose technical hurdles due to high homology. We have created an exome-wide resource that catalogs highly homologous regions that is tailored toward diagnostic applications. This resource was developed using a mappability-based approach tailored to current Sanger and NGS protocols. Gene-level and exon-level lists delineate regions that are difficult or impossible to analyze via standard NGS. These regions are ranked by degree of affectedness, annotated for medical relevance, and classified by the type of homology (within-gene, different functional gene, known pseudogene, uncharacterized noncoding region). Additionally, we provide a list of exons that cannot be analyzed by short-amplicon Sanger sequencing. This resource can help guide clinical test design, supplemental assay implementation, and results interpretation in the context of high homology. Genet Med 18 12, 1282–1289.

Published
2016

32. Imprinted genes in clinical exome sequencing: Review of 538 cases and exploration of mouse-human conservation in the identification of novel human disease loci

Author

Avni Santani, Samuel W. Baker, Elizabeth J. Bhoj, Farrah Rajabi, and Wen-Hann Tan

Subjects
0301 basic medicine, medicine.medical_specialty, 030105 genetics & heredity, Biology, Genomic Imprinting, Mice, 03 medical and health sciences, Databases, Genetic, Genetics, medicine, Animals, Humans, Exome, Imprinting (psychology), Conserved Sequence, Genetics (clinical), Exome sequencing, Whole Genome Sequencing, Genetic Diseases, Inborn, General Medicine, medicine.disease, Molecular diagnostics, Uniparental disomy, 030104 developmental biology, Genetic Loci, Mutation, DIRAS3, Medical genetics, Human genome, Genomic imprinting
Abstract

Human imprinting disorders cause a range of dysmorphic and neurocognitive phenotypes, and they may elude traditional molecular diagnosis such exome sequencing. The discovery of novel disorders related to imprinted genes has lagged behind traditional Mendelian disorders because current diagnostic technology, especially unbiased testing, has limited utility in their discovery. To identify novel imprinting disorders, we reviewed data for every human gene hypothesized to be imprinted, identified each mouse ortholog, determined its imprinting status in the mouse, and analyzed its function in humans and mice. We identified 17 human genes that are imprinted in both humans and mice, and have functional data in mice or humans to suggest that dysregulated expression would lead to an abnormal phenotype in humans. These 17 genes, along with known imprinted genes, were preferentially flagged 538 clinical exome sequencing tests. The identified genes were: DIRAS3 [1p31.3], TP73 [1p36.32], SLC22A3 [6q25.3], GRB10 [7p12.1], DDC [7p12.2], MAGI2 [7q21.11], PEG10 [7q21.3], PPP1R9A [7q21.3], CALCR [7q21.3], DLGAP2 [8p23.3], GLIS3 [9p24.2], INPP5F [10q26.11], ANO1 [11q13.3], SLC38A4 [12q13.11], GATM [15q21.1], PEG3 [19q13.43], and NLRP2 [19q13.42]. In the 538 clinical cases, eight cases (1.7%) reported variants in a causative known imprinted gene. There were 367/758 variants (48.4%) in imprinted genes that were not known to cause disease, but none of those variants met the criteria for clinical reporting. Imprinted disorders play a significant role in human disease, and additional human imprinted disorders remain to be discovered. Therefore, evolutionary conservation is a potential tool to identify novel genes involved in human imprinting disorders and to identify them in clinical testing.

Published
2020

33. Correction: The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

Author

Karin Weiss, Hayley P. Lazar, Alina Kurolap, Ariel F. Martinez, Tamar Paperna, Lior Cohen, Marie F. Smeland, Sandra Whalen, Solveig Heide, Boris Keren, Pauline Terhal, Melita Irving, Motoki Takaku, John D. Roberts, Robert M. Petrovich, Samantha A. Schrier Vergano, Amy Kenney, Hanne Hove, Elizabeth DeChene, Shane C. Quinonez, Estelle Colin, Alban Ziegler, Melissa Rumple, Mahim Jain, Danielle Monteil, Elizabeth R. Roeder, Kimberly Nugent, Arie van Haeringen, Michael Gambello, Avni Santani, Līvija Medne, Bryan Krock, Cara M. Skraban, Elaine H. Zackai, Holly A. Dubbs, Thomas Smol, Jamal Ghoumid, Michael J. Parker, Michael Wright, Peter Turnpenny, Jill Clayton-Smith, Kay Metcalfe, Hitoshi Kurumizaka, Bruce D. Gelb, Hagit Baris Feldman, Philippe M. Campeau, Maximilian Muenke, Paul A. Wade, and Katherine Lachlan

Subjects
Genetics (clinical)
Published
2020

34. E-POSTERS – EARLY ONSET MUSCLE DISEASE – CASE REPORTS

Author

Carsten G. Bönnemann, E. Denenberg, L. Medne, Mariarita Santi, J. Berkowitz, C. Skraban, A. Santani, Brenda Banwell, Elizabeth T. DeChene, and John F. Brandsema

Subjects
Pediatrics, medicine.medical_specialty, Muscle disease, Neurology, business.industry, Pediatrics, Perinatology and Child Health, Medicine, Neurology (clinical), business, Genetics (clinical), Early onset
Published
2019

36. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network

Author

Zouk, Hana, primary, Venner, Eric, additional, Lennon, Niall J., additional, Muzny, Donna M., additional, Abrams, Debra, additional, Adunyah, Samuel, additional, Albertson-Junkans, Ladia, additional, Ames, Darren C., additional, Appelbaum, Paul, additional, Aronson, Samuel, additional, Aufox, Sharon, additional, Babb, Lawrence J., additional, Balasubramanian, Adithya, additional, Bangash, Hana, additional, Basford, Melissa, additional, Bastarache, Lisa, additional, Baxter, Samantha, additional, Behr, Meckenzie, additional, Benoit, Barbara, additional, Bhoj, Elizabeth, additional, Bielinski, Suzette J., additional, Bland, Harris T., additional, Blout, Carrie, additional, Borthwick, Kenneth, additional, Bottinger, Erwin P., additional, Bowser, Mark, additional, Brand, Harrison, additional, Brilliant, Murray, additional, Brodeur, Wendy, additional, Caraballo, Pedro, additional, Carrell, David, additional, Carroll, Andrew, additional, Almoguera, Berta, additional, Castillo, Lisa, additional, Castro, Victor, additional, Chandanavelli, Gauthami, additional, Chiang, Theodore, additional, Chisholm, Rex L., additional, Christensen, Kurt D., additional, Chung, Wendy, additional, Chute, Christopher G., additional, City, Brittany, additional, Cobb, Beth L., additional, Connolly, John J., additional, Crane, Paul, additional, Crew, Katherine, additional, Crosslin, David, additional, De Andrade, Mariza, additional, De la Cruz, Jessica, additional, Denson, Shawn, additional, Denny, Josh, additional, DeSmet, Tim, additional, Dikilitas, Ozan, additional, Friedrich, Christopher, additional, Fullerton, Stephanie M., additional, Funke, Birgit, additional, Gabriel, Stacey, additional, Gainer, Vivian, additional, Gharavi, Ali, additional, Glazer, Andrew M., additional, Glessner, Joseph T., additional, Goehringer, Jessica, additional, Gordon, Adam S., additional, Graham, Chet, additional, Green, Robert C., additional, Gundelach, Justin H., additional, Dayal, Jyoti, additional, Hain, Heather S., additional, Hakonarson, Hakon, additional, Harden, Maegan V., additional, Harley, John, additional, Harr, Margaret, additional, Hartzler, Andrea, additional, Hayes, M. Geoffrey, additional, Hebbring, Scott, additional, Henrikson, Nora, additional, Hershey, Andrew, additional, Hoell, Christin, additional, Holm, Ingrid, additional, Howell, Kayla M., additional, Hripcsak, George, additional, Hu, Jianhong, additional, Jarvik, Gail P., additional, Jayaseelan, Joy C., additional, Jiang, Yunyun, additional, Joo, Yoonjung Yoonie, additional, Jose, Sheethal, additional, Josyula, Navya Shilpa, additional, Justice, Anne E., additional, Kalla, Sara E., additional, Kalra, Divya, additional, Karlson, Elizabeth, additional, Kelly, Melissa A., additional, Keating, Brendan J., additional, Kenny, Eimear E., additional, Key, Dustin, additional, Kiryluk, Krzysztof, additional, Kitchner, Terrie, additional, Klanderman, Barbara, additional, Klee, Eric, additional, Kochan, David C., additional, Korchina, Viktoriya, additional, Kottyan, Leah, additional, Kovar, Christie, additional, Kudalkar, Emily, additional, Kullo, Iftikhar J., additional, Lammers, Philip, additional, Larson, Eric B., additional, Lebo, Matthew S., additional, Leduc, Magalie, additional, Lee, Ming Ta (Michael), additional, Leppig, Kathleen A., additional, Leslie, Nancy D., additional, Li, Rongling, additional, Liang, Wayne H., additional, Lin, Chiao-Feng, additional, Linder, Jodell, additional, Lindor, Noralane M., additional, Lingren, Todd, additional, Linneman, James G., additional, Liu, Cong, additional, Liu, Wen, additional, Liu, Xiuping, additional, Lynch, John, additional, Lyon, Hayley, additional, Macbeth, Alyssa, additional, Mahadeshwar, Harshad, additional, Mahanta, Lisa, additional, Malin, Brad, additional, Manolio, Teri, additional, Marasa, Maddalena, additional, Marsolo, Keith, additional, Dinsmore, Michael J., additional, Dodge, Sheila, additional, Hynes, Elizabeth Duffy, additional, Dunlea, Phil, additional, Edwards, Todd L., additional, Eng, Christine M., additional, Fasel, David, additional, Fedotov, Alex, additional, Feng, Qiping, additional, Fleharty, Mark, additional, Foster, Andrea, additional, Freimuth, Robert, additional, McGowan, Michelle L., additional, McNally, Elizabeth, additional, Meldrim, Jim, additional, Mentch, Frank, additional, Mosley, Jonathan, additional, Mukherjee, Shubhabrata, additional, Mullen, Thomas E., additional, Muniz, Jesse, additional, Murdock, David R., additional, Murphy, Shawn, additional, Murugan, Mullai, additional, Myers, Melanie F., additional, Namjou, Bahram, additional, Ni, Yizhao, additional, Obeng, Aniwaa Owusu, additional, Onofrio, Robert C., additional, Taylor, Casey Overby, additional, Person, Thomas N., additional, Peterson, Josh F., additional, Petukhova, Lynn, additional, Pisieczko, Cassandra J., additional, Pratap, Siddharth, additional, Prows, Cynthia A., additional, Puckelwartz, Megan J., additional, Rahm, Alanna Kulchak, additional, Raj, Ritika, additional, Ralston, James D., additional, Ramaprasan, Arvind, additional, Ramirez, Andrea, additional, Rasmussen, Luke, additional, Rasmussen-Torvik, Laura, additional, Rasouly, Hila Milo, additional, Raychaudhuri, Soumya, additional, Ritchie, Marylyn D., additional, Rives, Catherine, additional, Riza, Beenish, additional, Roden, Dan, additional, Rosenthal, Elisabeth A., additional, Santani, Avni, additional, Schaid, Dan, additional, Scherer, Steven, additional, Scott, Stuart, additional, Scrol, Aaron, additional, Sengupta, Soumitra, additional, Shang, Ning, additional, Sharma, Himanshu, additional, Sharp, Richard R., additional, Singh, Rajbir, additional, Sleiman, Patrick M.A., additional, Slowik, Kara, additional, Smith, Joshua C., additional, Smith, Maureen E., additional, Smoller, Jordan W., additional, Sohn, Sunghwan, additional, Stanaway, Ian B., additional, Starren, Justin, additional, Stroud, Mary, additional, Su, Jessica, additional, Tolwinski, Kasia, additional, Van Driest, Sara L., additional, Vargas, Sean M., additional, Varugheese, Matthew, additional, Veenstra, David, additional, Verbitsky, Miguel, additional, Vicente, Gina, additional, Wagner, Michael, additional, Walker, Kimberly, additional, Walunas, Theresa, additional, Wang, Liwen, additional, Wang, Qiaoyan, additional, Wei, Wei-Qi, additional, Weiss, Scott T., additional, Wiesner, Georgia L., additional, Wells, Quinn, additional, Weng, Chunhua, additional, White, Peter S., additional, Wiley, Ken L., additional, Williams, Janet L., additional, Williams, Marc S., additional, Wilson, Michael W., additional, Witkowski, Leora, additional, Woods, Laura Allison, additional, Woolf, Betty, additional, Wu, Tsung-Jung, additional, Wynn, Julia, additional, Yang, Yaping, additional, Yi, Victoria, additional, Zhang, Ge, additional, Zhang, Lan, additional, Rehm, Heidi L., additional, and Gibbs, Richard A., additional

Published
2019
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37. Designing and Implementing NGS Tests for Inherited Disorders

Author

Santani, Avni, primary, Simen, Birgitte B., additional, Briggs, Marian, additional, Lebo, Matthew, additional, Merker, Jason D., additional, Nikiforova, Marina, additional, Vasalos, Patricia, additional, Voelkerding, Karl, additional, Pfeifer, John, additional, and Funke, Birgit, additional

Published
2019
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38. Automated Clinical Exome Reanalysis Reveals Novel Diagnoses

Author

Baker, Samuel W., primary, Murrell, Jill R., additional, Nesbitt, Addie I., additional, Pechter, Kieran B., additional, Balciuniene, Jorune, additional, Zhao, Xiaonan, additional, Yu, Zhenming, additional, Denenberg, Elizabeth H., additional, DeChene, Elizabeth T., additional, Wilkens, Alisha B., additional, Bhoj, Elizabeth J., additional, Guan, Qiaoning, additional, Dulik, Matthew C., additional, Conlin, Laura K., additional, Abou Tayoun, Ahmad N., additional, Luo, Minjie, additional, Wu, Chao, additional, Cao, Kajia, additional, Sarmady, Mahdi, additional, Bedoukian, Emma C., additional, Tarpinian, Jennifer, additional, Medne, Livija, additional, Skraban, Cara M., additional, Deardorff, Matthew A., additional, Krantz, Ian D., additional, Krock, Bryan L., additional, and Santani, Avni B., additional

Published
2019
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39. Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss

Author

Sheppard, Sarah, primary, Biswas, Sawona, additional, Li, Mindy H., additional, Jayaraman, Vijayakumar, additional, Slack, Ian, additional, Romasko, Edward J., additional, Sasson, Ariella, additional, Brunton, Joshua, additional, Rajagopalan, Ramakrishnan, additional, Sarmady, Mahdi, additional, Abrudan, Jenica L., additional, Jairam, Sowmya, additional, DeChene, Elizabeth T., additional, Ying, Xiahoan, additional, Choi, Jiwon, additional, Wilkens, Alisha, additional, Raible, Sarah E., additional, Scarano, Maria I., additional, Santani, Avni, additional, Pennington, Jeffrey W., additional, Luo, Minjie, additional, Conlin, Laura K., additional, Devkota, Batsal, additional, Dulik, Matthew C., additional, Spinner, Nancy B., additional, and Krantz, Ian D., additional

Published
2018
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40. AUDIOME: a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss

Author

Guan, Qiaoning, primary, Balciuniene, Jorune, additional, Cao, Kajia, additional, Fan, Zhiqian, additional, Biswas, Sawona, additional, Wilkens, Alisha, additional, Gallo, Daniel J, additional, Bedoukian, Emma, additional, Tarpinian, Jennifer, additional, Jayaraman, Pushkala, additional, Sarmady, Mahdi, additional, Dulik, Matthew, additional, Santani, Avni, additional, Spinner, Nancy, additional, Abou Tayoun, Ahmad N, additional, Krantz, Ian D, additional, Conlin, Laura K, additional, and Luo, Minjie, additional

Published
2018
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41. NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Author

Schanze, Ina, primary, Bunt, Jens, additional, Lim, Jonathan W.C., additional, Schanze, Denny, additional, Dean, Ryan J., additional, Alders, Marielle, additional, Blanchet, Patricia, additional, Attié-Bitach, Tania, additional, Berland, Siren, additional, Boogert, Steven, additional, Boppudi, Sangamitra, additional, Bridges, Caitlin J., additional, Cho, Megan T., additional, Dobyns, William B., additional, Donnai, Dian, additional, Douglas, Jessica, additional, Earl, Dawn L., additional, Edwards, Timothy J., additional, Faivre, Laurence, additional, Fregeau, Brieana, additional, Genevieve, David, additional, Gérard, Marion, additional, Gatinois, Vincent, additional, Holder-Espinasse, Muriel, additional, Huth, Samuel F., additional, Izumi, Kosuke, additional, Kerr, Bronwyn, additional, Lacaze, Elodie, additional, Lakeman, Phillis, additional, Mahida, Sonal, additional, Mirzaa, Ghayda M., additional, Morgan, Sian M., additional, Nowak, Catherine, additional, Peeters, Hilde, additional, Petit, Florence, additional, Pilz, Daniela T., additional, Puechberty, Jacques, additional, Reinstein, Eyal, additional, Rivière, Jean-Baptiste, additional, Santani, Avni B., additional, Schneider, Anouck, additional, Sherr, Elliott H., additional, Smith-Hicks, Constance, additional, Wieland, Ilse, additional, Zackai, Elaine, additional, Zhao, Xiaonan, additional, Gronostajski, Richard M., additional, Zenker, Martin, additional, and Richards, Linda J., additional

Published
2018
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42. Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

Author

Stephen G. Miller, J. William Gaynor, Jeffery P. Jacobs, Andrew M. Atz, Gail P. Jarvik, Bradley S. Marino, Christian Pizarro, Seema Mital, William T. Mahle, Nicole S. Wilder, Cammon B. Arrington, Avni Santani, David C. Bellinger, Jane W. Newburger, Amber A. Burt, Alan B. Lewis, Teresa M. Lee, Nancy S. Ghanayem, Mark W. Russell, Daniel Seung Kim, and Chitra Ravishankar

Subjects
Heart Defects, Congenital, Male, Apolipoprotein E, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Apolipoprotein E2, Traumatic brain injury, Developmental Disabilities, Neuropsychological Tests, 030204 cardiovascular system & hematology, Nervous System, Bayley Scales of Infant Development, 03 medical and health sciences, Child Development, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, 030225 pediatrics, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Cardiac Surgical Procedures, Allele, business.industry, Age Factors, Infant, Newborn, Infant, Reproducibility of Results, medicine.disease, 3. Good health, Cardiac surgery, Phenotype, Predictive value of tests, Anesthesia, Multivariate Analysis, Cohort, Female, Surgery, business, Cardiology and Cardiovascular Medicine
Abstract

Objective Apolipoprotein E ( APOE ) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE e2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. Methods The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. Results Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE e2 allele was associated with a lower PDI score ( P = .038). Patients with the e2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the e2 allele was present in only 11% of the patients. There was a marginal effect of the e2 allele on MDI scores ( P = .058). Conclusions These data validate the association of the APOE e2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.

Published
2014
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43. Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers

Author

Sanghvi, Rashesh V., primary, Buhay, Christian J., additional, Powell, Bradford C., additional, Tsai, Ellen A., additional, Dorschner, Michael O., additional, Hong, Celine S., additional, Lebo, Matthew S., additional, Sasson, Ariella, additional, Hanna, David S., additional, McGee, Sean, additional, Bowling, Kevin M., additional, Cooper, Gregory M., additional, Gray, David E., additional, Lonigro, Robert J., additional, Dunford, Andrew, additional, Brennan, Christine A., additional, Cibulskis, Carrie, additional, Walker, Kimberly, additional, Carneiro, Mauricio O., additional, Sailsbery, Joshua, additional, Hindorff, Lucia A., additional, Robinson, Dan R., additional, Santani, Avni, additional, Sarmady, Mahdi, additional, Rehm, Heidi L., additional, Biesecker, Leslie G., additional, Nickerson, Deborah A., additional, Hutter, Carolyn M., additional, Garraway, Levi, additional, Muzny, Donna M., additional, and Wagle, Nikhil, additional

Published
2018
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44. De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder

Author

Gregor, Anne, primary, Sadleir, Lynette G., additional, Asadollahi, Reza, additional, Azzarello-Burri, Silvia, additional, Battaglia, Agatino, additional, Ousager, Lilian Bomme, additional, Boonsawat, Paranchai, additional, Bruel, Ange-Line, additional, Buchert, Rebecca, additional, Calpena, Eduardo, additional, Cogné, Benjamin, additional, Dallapiccola, Bruno, additional, Distelmaier, Felix, additional, Elmslie, Frances, additional, Faivre, Laurence, additional, Haack, Tobias B., additional, Harrison, Victoria, additional, Henderson, Alex, additional, Hunt, David, additional, Isidor, Bertrand, additional, Joset, Pascal, additional, Kumada, Satoko, additional, Lachmeijer, Augusta M.A., additional, Lees, Melissa, additional, Lynch, Sally Ann, additional, Martinez, Francisco, additional, Matsumoto, Naomichi, additional, McDougall, Carey, additional, Mefford, Heather C., additional, Miyake, Noriko, additional, Myers, Candace T., additional, Moutton, Sébastien, additional, Nesbitt, Addie, additional, Novelli, Antonio, additional, Orellana, Carmen, additional, Rauch, Anita, additional, Rosello, Monica, additional, Saida, Ken, additional, Santani, Avni B., additional, Sarkar, Ajoy, additional, Scheffer, Ingrid E., additional, Shinawi, Marwan, additional, Steindl, Katharina, additional, Symonds, Joseph D., additional, Zackai, Elaine H., additional, Reis, André, additional, Sticht, Heinrich, additional, and Zweier, Christiane, additional

Published
2018
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45. Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Author

Gibson, Kristin McDonald, primary, Nesbitt, Addie, additional, Cao, Kajia, additional, Yu, Zhenming, additional, Denenberg, Elizabeth, additional, DeChene, Elizabeth, additional, Guan, Qiaoning, additional, Bhoj, Elizabeth, additional, Zhou, Xiangdong, additional, Zhang, Bo, additional, Wu, Chao, additional, Dubbs, Holly, additional, Wilkens, Alisha, additional, Medne, Livija, additional, Bedoukian, Emma, additional, White, Peter S., additional, Pennington, Jeffrey, additional, Lou, Minjie, additional, Conlin, Laura, additional, Monos, Dimitri, additional, Sarmady, Mahdi, additional, Marsh, Eric, additional, Zackai, Elaine, additional, Spinner, Nancy, additional, Krantz, Ian, additional, Deardorff, Matt, additional, and Santani, Avni, additional

Published
2018
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46. Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila

Author

Straub, Jonas, primary, Konrad, Enrico D.H., additional, Grüner, Johanna, additional, Toutain, Annick, additional, Bok, Levinus A., additional, Cho, Megan T., additional, Crawford, Heather P., additional, Dubbs, Holly, additional, Douglas, Ganka, additional, Jobling, Rebekah, additional, Johnson, Diana, additional, Krock, Bryan, additional, Mikati, Mohamad A., additional, Nesbitt, Addie, additional, Nicolai, Joost, additional, Phillips, Meredith, additional, Poduri, Annapurna, additional, Ortiz-Gonzalez, Xilma R., additional, Powis, Zöe, additional, Santani, Avni, additional, Smith, Lacey, additional, Stegmann, Alexander P.A., additional, Stumpel, Constance, additional, Vreeburg, Maaike, additional, Fliedner, Anna, additional, Gregor, Anne, additional, Sticht, Heinrich, additional, and Zweier, Christiane, additional

Published
2018
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47. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Küry, Sébastien, primary, van Woerden, Geeske M., additional, Besnard, Thomas, additional, Proietti Onori, Martina, additional, Latypova, Xénia, additional, Towne, Meghan C., additional, Cho, Megan T., additional, Prescott, Trine E., additional, Ploeg, Melissa A., additional, Sanders, Stephan, additional, Stessman, Holly A.F., additional, Pujol, Aurora, additional, Distel, Ben, additional, Robak, Laurie A., additional, Bernstein, Jonathan A., additional, Denommé-Pichon, Anne-Sophie, additional, Lesca, Gaëtan, additional, Sellars, Elizabeth A., additional, Berg, Jonathan, additional, Carré, Wilfrid, additional, Busk, Øyvind Løvold, additional, van Bon, Bregje W.M., additional, Waugh, Jeff L., additional, Deardorff, Matthew, additional, Hoganson, George E., additional, Bosanko, Katherine B., additional, Johnson, Diana S., additional, Dabir, Tabib, additional, Holla, Øystein Lunde, additional, Sarkar, Ajoy, additional, Tveten, Kristian, additional, de Bellescize, Julitta, additional, Braathen, Geir J., additional, Terhal, Paulien A., additional, Grange, Dorothy K., additional, van Haeringen, Arie, additional, Lam, Christina, additional, Mirzaa, Ghayda, additional, Burton, Jennifer, additional, Bhoj, Elizabeth J., additional, Douglas, Jessica, additional, Santani, Avni B., additional, Nesbitt, Addie I., additional, Helbig, Katherine L., additional, Andrews, Marisa V., additional, Begtrup, Amber, additional, Tang, Sha, additional, van Gassen, Koen L.I., additional, Juusola, Jane, additional, Foss, Kimberly, additional, Enns, Gregory M., additional, Moog, Ute, additional, Hinderhofer, Katrin, additional, Paramasivam, Nagarajan, additional, Lincoln, Sharyn, additional, Kusako, Brandon H., additional, Lindenbaum, Pierre, additional, Charpentier, Eric, additional, Nowak, Catherine B., additional, Cherot, Elouan, additional, Simonet, Thomas, additional, Ruivenkamp, Claudia A.L., additional, Hahn, Sihoun, additional, Brownstein, Catherine A., additional, Xia, Fan, additional, Schmitt, Sébastien, additional, Deb, Wallid, additional, Bonneau, Dominique, additional, Nizon, Mathilde, additional, Quinquis, Delphine, additional, Chelly, Jamel, additional, Rudolf, Gabrielle, additional, Sanlaville, Damien, additional, Parent, Philippe, additional, Gilbert-Dussardier, Brigitte, additional, Toutain, Annick, additional, Sutton, Vernon R., additional, Thies, Jenny, additional, Peart-Vissers, Lisenka E.L.M., additional, Boisseau, Pierre, additional, Vincent, Marie, additional, Grabrucker, Andreas M., additional, Dubourg, Christèle, additional, Tan, Wen-Hann, additional, Verbeek, Nienke E., additional, Granzow, Martin, additional, Santen, Gijs W.E., additional, Shendure, Jay, additional, Isidor, Bertrand, additional, Pasquier, Laurent, additional, Redon, Richard, additional, Yang, Yaping, additional, State, Matthew W., additional, Kleefstra, Tjitske, additional, Cogné, Benjamin, additional, Petrovski, Slavé, additional, Retterer, Kyle, additional, Eichler, Evan E., additional, Rosenfeld, Jill A., additional, Agrawal, Pankaj B., additional, Bézieau, Stéphane, additional, Odent, Sylvie, additional, Elgersma, Ype, additional, and Mercier, Sandra, additional

Published
2017
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48. Correction: Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Author

Kristin McDonald, Gibson, Addie, Nesbitt, Kajia, Cao, Zhenming, Yu, Elizabeth, Denenberg, Elizabeth, DeChene, Qiaoning, Guan, Elizabeth, Bhoj, Xiangdong, Zhou, Bo, Zhang, Chao, Wu, Holly, Dubbs, Alisha, Wilkens, Livija, Medne, Emma, Bedoukian, Peter S, White, Jeffrey, Pennington, Minjie, Luo, Laura, Conlin, Dimitri, Monos, Mahdi, Sarmady, Eric, Marsh, Elaine, Zackai, Nancy, Spinner, Ian, Krantz, Matt, Deardorff, and Avni, Santani

Subjects
Genetics (clinical)
Abstract

In the published version of this article, the name of the 18th author was misspelled as Minjie Lou. The correct name is Minjie Luo. The authors regret the error.

Published
2018

49. A rapid, noninvasive immunoassay for frataxin: Utility in assessment of Friedreich ataxia

Author

Michael F. Marusich, Eric Deutsch, Catherine A. Stolle, Jennifer Farmer, David A. Lynch, Avni Santani, and Susan Perlman

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Ataxia, Adolescent, Endocrinology, Diabetes and Metabolism, Buccal swab, Population, Biology, Sensitivity and Specificity, Biochemistry, Article, Endocrinology, Iron-Binding Proteins, Genetics, medicine, Humans, Multiplex ligation-dependent probe amplification, Child, education, Molecular Biology, Immunoassay, education.field_of_study, Point mutation, Mouth Mucosa, Reproducibility of Results, Molecular biology, Friedreich Ataxia, Frataxin, biology.protein, Biomarker (medicine), Female, medicine.symptom, Trinucleotide Repeat Expansion, Trinucleotide repeat expansion
Abstract

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by reduced amounts of the mitochondrial protein frataxin. Frataxin levels in research studies are typically measured via Western blot analysis from patient fibroblasts, lymphocytes, or muscle biopsies; none of these is ideal for rapid detection in large scale clinical studies. Recently, a rapid, non-invasive lateral-flow immunoassay was developed to accurately measure picogram levels of frataxin protein and shown to distinguish lymphoblastoid cells from FRDA carriers, patients and controls. We expanded the immunoassay to measure frataxin directly in buccal cells and whole blood from a large cohort of controls, known carriers and patients typical of a clinical trial population. The assay in buccal cells shared a similar degree of variability with previous studies conducted in lymphoblastoid cells (~10% coefficient of variation in controls). Significant differences in frataxin protein quantity were seen between the mean group values of controls, carriers, and patient buccal cells (100, 50.2, and 20.9% of control, respectively) and in protein extracted from whole blood (100, 75.3, and 32.2%, respectively), although there was some overlap between the groups. In addition, frataxin levels were inversely related to GAA repeat length and correlated directly with age of onset. Subjects with one expanded GAA repeat and an identified frataxin point mutation also carried frataxin levels in the disease range. Some patients displaying an FRDA phenotype but carrying only a single identifiable mutation had frataxin levels in the FRDA patient range. One patient from this group has a novel deletion that included exons 2 and 3 of the FXN gene based on multiplex ligation-dependent probe amplification (MLPA) analysis of the FXN gene. The lateral flow immunoassay may be a useful means to non-invasively assess frataxin levels repetitively with minimal discomfort in FRDA patients in specific situations such as clinical trials, and as a complementary diagnostic tool to aid in identification and characterization of atypical patients.

Published
2010

50. Involvement of the PI3K/AKT pathway in the hypoglycemic effects of saponins from Helicteres isora

Author

Sanjay Vir, Florian Lang, Mamta B. Shah, Kamlesh K. Bhutani, Dev D. Santani, Shefalee K. Bhavsar, Michael Föller, and Shuchen Gu

Subjects
Helicteres isora, Blotting, Western, Sapogenin, Pharmacology, Mass Spectrometry, Cell Line, Mice, Phosphatidylinositol 3-Kinases, GSK-3, Drug Discovery, Animals, Hypoglycemic Agents, Phosphorylation, Glycogen synthase, Protein kinase A, Malvaceae, Protein kinase B, Chromatography, High Pressure Liquid, PI3K/AKT/mTOR pathway, DNA Primers, Base Sequence, biology, Reverse Transcriptase Polymerase Chain Reaction, Saponins, musculoskeletal system, biology.organism_classification, Rats, Biochemistry, biology.protein, Insulin Resistance, Proto-Oncogene Proteins c-akt
Abstract

Aim of the study Saponins from Helicteres isora have previously been shown to exert antidiabetic effects. The present study explored the underlying mechanisms in C2C12 skeletal muscle cells. Materials and methods C2C12 cells were incubated with saponins and sapogenin followed by Western blotting and immunofluorescence analysis. Results Western blotting revealed that incubation with saponins (100 μg/ml) and sapogenin (100 μg/ml) induced the phosphorylation of the phosphatidylinositol-3-kinase (PI3K) as well as of the downstream targets protein kinase B/Akt (at Ser473) and glycogen synthase kinase GSK-3α/β (at Ser21/9) in a time-dependent manner. In contrast, no phosphorylation of the AMP-sensitive kinase AMPK (at Thr172) was observed. Within 48 h saponins/sapogenin treatment further increased the protein abundance of the insulin-sensitive glucose transporter Glut4. Confocal microscopy confirmed that saponins/sapogenin treatment stimulated Akt phosphorylation and revealed that the treatment was followed by translocation of Glut4 into the cell membrane of C2C12 muscle cells. Conclusions Saponins and sapogenin activate the PI3K/Akt pathway thus leading to phosphorylation and inactivation of GSK-3α/β with subsequent stimulation of glycogen synthesis as well as increase of Glut4-dependent glucose transport across the cell membrane.

Published
2009

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