125 results on '"Szuto A"'
Search Results
2. O05: A micro-costing and cost-effectiveness analysis of genome sequencing vs exome sequencing in pediatric rare diseases
- Author
-
Wendy Ungar, Vercancy Wu, Christian Marshall, Jackie Hwang, Robin Hayeems, Kate Tsiplova, Meredith Gillespie, Anna Szuto, Caitlin Chisholm, Dimitri Stavropoulos, Viji Venkataramanan, Bowen Xiao, Sheena Li, Gregory Costain, Melanie Beaulieu Bergeron, Sarah Sawyer, Lynette Lau, Lijia Huang, Roberto Mendoza-Londono, Brian Smith, Edward Higginbotham, Martin Somerville, and Kym Boycott
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2024
- Full Text
- View/download PDF
3. P540: Genome-wide Sequencing Ontario (GSO): Canada’s first provincial clinical genome-wide sequencing service
- Author
-
Meredith Gillespie, Robin Hayeems, Christian Marshall, Anna Szuto, Caitlin Chisholm, James Stavropoulos, Lijia Huang, Lynette Lau, Wilson Sung, Melanie Beaulieu Bergeron, Ted Higginbotham, Meredith Curtis, Venuja Sriretnakumar, Hassan Zaidi, Emma Hitchcock, Audrey Schaffer, Taila Hartley, Sarah Sawyer, Wendy Ungar, Gregory Costain, Roberto Mendoza-Londono, Anna Pan, Jennifer Keating, Diana Matviychuk, Tamara Braid, Niri Carroll, Martin Somerville, and Kym Boycott
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2024
- Full Text
- View/download PDF
4. P597: All for One Clinical Genomics Network: Linking Canadian diagnostic laboratories to share genome-wide sequencing data to support rare disease diagnosis
- Author
-
E. Magda Price, Meredith Gillespie, Caitlin Chisholm, Ruben Attali, Talia Silver, Anna Szuto, GSO Study Team, Jacques Michaud, Dennis Bulman, Jordan Lerner-Ellis, Ma'n Zawati, Vincent Ferretti, Francois Bernier, Christian Marshall, and Kym Boycott
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2024
- Full Text
- View/download PDF
5. P616: Genome-wide Sequencing Ontario (GSO): Insight into Ontario’s rare disease landscape
- Author
-
Meredith Gillespie, Robin Hayeems, Christian Marshall, Anna Szuto, Caitlin Chisholm, Wendy Ungar, James Stavropoulos, Lijia Huang, Viji Venkataramanan, Lynette Lau, Wilson Sung, Melanie Beaulieu Bergeron, Ted Higginbotham, Meredith Curtis, Venuja Sriretnakumar, Hassan Zaidi, Emma Hitchcock, Audrey Schaffer, Sarah Sawyer, Gregory Costain, Roberto Mendoza-Londono, Martin Somerville, Kym Boycott, and Taila Hartley
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2024
- Full Text
- View/download PDF
6. P642: Development and deployment of clinical genome sequencing using a cloud-based platform
- Author
-
Lynette Lau, Edward Higginbotham, Wilson Sung, Venuja Sriretnakumar, Meredith Curtis, Caitlin Chisholm, Meredith Gillespie, Anna Pan, Sean Kim, Sean Simko, E. Magda Price, Marianne Eliou, Anna Szuto, Michelle Axford, Martin Somerville, Kym Boycott, Jean McGowan-Jordan, Melaine Beaulieu Bergeron, James Stavropoulos, Lijia Huang, and Christian Marshall
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2024
- Full Text
- View/download PDF
7. P866: Exploring the impact of secondary findings in a cohort of patients and families receiving genome-wide sequencing
- Author
-
Katharine Fooks, Lydia Vermeer, Elise Poole, Stephanie Luca, Riyana Babul-Hirji, Lauren Chad, David Chitayat, Michael Mackley, Marci Schwartz, Wendy Ungar, Robin Hayeems, Secondary Findings Study Team, Joyce Yan, Abigail Hansen, Viji Venkataramanan, Daniel Assamad, Christian Marshall, Meredith Gillespie, Anna Szuto, Caitlin Chisholm, James Stavropoulos, Lijia Huang, Olga Jarinova, Lynette Lau, Whiwon Lee, Lauren Badalato, Tugce Balci, Cara Inglese, Virginie Beausejour Ladouceur, Chantal Morel, Julie Richer, Mark Tarnopolsky, Anita Villani, Laura Zahavich, Olivia Moran, Sarah Sawyer, Roberto Mendoza-Londono, Martin Somerville, and Kym Boycott
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2024
- Full Text
- View/download PDF
8. P873: 'If you look for a problem, you’ll find one': A qualitative study to understand why parents/adult patients decline secondary findings
- Author
-
Abigail Hansen, Stephanie Luca, Olivia Moran, Riyana Babul-Hirji, Joyce Yan, Katharine Fooks, Viji Venkataramanan, Wendy Ungar, Robin Hayeems, Secondary Findings Study Team, Elise Poole, Daniel Assamad, Pooja Banglorewala, Lydia Vermeer, Christian Marshall, Meredith Gillespie, Anna Szuto, Caitlin Chisholm, James Stavropoulos, Lijia Huang, Olga Jarinova, Lynette Lau, Whiwon Lee, Lauren Badalato, Tugce Balci, Lauren Chad, Cara Inglese, Virginie Ladouceur, Michael Mackley, Chantal Morel, Julie Richer, Mark Tarnopolsky, Anita Villani, Laura Zahavich, Sarah Sawyer, Roberto Mendoza-Londono, Martin Somerville, and Kym Boycott
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2024
- Full Text
- View/download PDF
9. Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study
- Author
-
Boycott, Kym, Brudno, Michael, Bernier, Francois, van Karnebeek, Clara, Dyment, David, Kernohan, Kristin, Innes, Micheil, Lamont, Ryan, Parboosingh, Jillian, Marshall, Deborah, Marshall, Christian, Mendoza, Roberto, Dowling, James, Hayeems, Robin, Knoppers, Bartha, Lehman, Anna, Mostafavi, Sara, Hartley, Taila, Acker, Meryl, Fooks, Katharine, Gillespie, Meredith K., Price, E. Magda, Graham, Ian D., White-Brown, Alexandre, MacKay, Layla, Macdonald, Stella K., Brady, Lauren, Hui, Angela Y., Andrews, Joseph D., Chowdhury, Ashfia, Wall, Erika, Soubry, Élisabeth, Ediae, Grace U., Rojas, Samantha, Assamad, Daniel, Tarnopolsky, Mark, Sawyer, Sarah L., Chisholm, Caitlin, Lemire, Gabrielle, Amburgey, Kimberly, Lazier, Joanna, Mendoza-Londono, Roberto, Dowling, James J., Balci, Tugce B., Armour, Christine M., Bhola, Priya T., Costain, Gregory, Dupuis, Lucie, Carter, Melissa, Badalato, Lauren, Richer, Julie, Boswell-Patterson, Christie, Kannu, Peter, Cordeiro, Dawn, Warman-Chardon, Jodi, Graham, Gail, Siu, Victoria Mok, Cytrynbaum, Cheryl, Rusnak, Alison, Aul, Ritu B., Yoon, Grace, Gonorazky, Hernan, McNiven, Vanda, Mercimek-Andrews, Saadet, Guerin, Andrea, Deshwar, Ashish R., Marwaha, Ashish, Weksberg, Rosanna, Karp, Natalya, Campbell, Maggie, Al-Qattan, Sarah, Shuen, Andrew Y., Inbar-Feigenberg, Michal, Cohn, Ronald, Szuto, Anna, Inglese, Cara, Poirier, Myriam, Chad, Lauren, Potter, Beth, and Boycott, Kym M.
- Published
- 2024
- Full Text
- View/download PDF
10. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change
- Author
-
Marshall, Christian, Meng, Linyan, Jobanputra, Vaidehi, Taft, Ryan, Ashley, Euan, Nakouzi, Ghunwa, Shen, Wei, Kingsmore, Stephen, Rehm, Heidi, Rehm, Heidi L., Alaimo, Joseph T., Aradhya, Swaroop, Bayrak-Toydemir, Pinar, Best, Hunter, Brandon, Rhonda, Buchan, Jillian G., Chao, Elizabeth C., Chen, Elaine, Clifford, Jacob, Cohen, Ana S.A., Conlin, Laura K., Das, Soma, Davis, Kyle W., del Gaudio, Daniela, Del Viso, Florencia, DiVincenzo, Christina, Eisenberg, Marcia, Guidugli, Lucia, Hammer, Monia B., Harrison, Steven M., Hatchell, Kathryn E., Dyer, Lindsay Havens, Hoang, Lily U., Holt, James M., Karbassi, Izabela D., Kearney, Hutton M., Kelly, Melissa A., Kelly, Jacob M., Kluge, Michelle L., Komala, Timothy, Kruszka, Paul, Lau, Lynette, Lebo, Matthew S., Marshall, Christian R., McKnight, Dianalee, McWalter, Kirsty, Meng, Yan, Nagan, Narasimhan, Neckelmann, Christian S., Neerman, Nir, Niu, Zhiyv, Paolillo, Vitoria K., Paolucci, Sarah A., Perry, Denise, Pesaran, Tina, Radtke, Kelly, Rasmussen, Kristen J., Retterer, Kyle, Saunders, Carol J., Spiteri, Elizabeth, Stanley, Christine, Szuto, Anna, Taft, Ryan J., Thiffault, Isabelle, Thomas, Brittany C., Thomas-Wilson, Amanda, Thorpe, Erin, Tidwell, Timothy J., Towne, Meghan C., and Zouk, Hana
- Published
- 2023
- Full Text
- View/download PDF
11. Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study
- Author
-
Hartley, Taila, primary, Marshall, Deborah, additional, Acker, Meryl, additional, Fooks, Katharine, additional, Gillespie, Meredith K., additional, Price, E. Magda, additional, Graham, Ian D., additional, White-Brown, Alexandre, additional, MacKay, Layla, additional, Macdonald, Stella K., additional, Brady, Lauren, additional, Hui, Angela Y., additional, Andrews, Joseph D., additional, Chowdhury, Ashfia, additional, Wall, Erika, additional, Soubry, Élisabeth, additional, Ediae, Grace U., additional, Rojas, Samantha, additional, Assamad, Daniel, additional, Dyment, David, additional, Tarnopolsky, Mark, additional, Sawyer, Sarah L., additional, Chisholm, Caitlin, additional, Lemire, Gabrielle, additional, Amburgey, Kimberly, additional, Lazier, Joanna, additional, Mendoza-Londono, Roberto, additional, Dowling, James J., additional, Balci, Tugce B., additional, Armour, Christine M., additional, Bhola, Priya T., additional, Costain, Gregory, additional, Dupuis, Lucie, additional, Carter, Melissa, additional, Badalato, Lauren, additional, Richer, Julie, additional, Boswell-Patterson, Christie, additional, Kannu, Peter, additional, Cordeiro, Dawn, additional, Warman-Chardon, Jodi, additional, Graham, Gail, additional, Siu, Victoria Mok, additional, Cytrynbaum, Cheryl, additional, Rusnak, Alison, additional, Aul, Ritu B., additional, Yoon, Grace, additional, Gonorazky, Hernan, additional, McNiven, Vanda, additional, Mercimek-Andrews, Saadet, additional, Guerin, Andrea, additional, Deshwar, Ashish R., additional, Marwaha, Ashish, additional, Weksberg, Rosanna, additional, Karp, Natalya, additional, Campbell, Maggie, additional, Al-Qattan, Sarah, additional, Shuen, Andrew Y., additional, Inbar-Feigenberg, Michal, additional, Cohn, Ronald, additional, Szuto, Anna, additional, Inglese, Cara, additional, Poirier, Myriam, additional, Chad, Lauren, additional, Potter, Beth, additional, Boycott, Kym M., additional, Hayeems, Robin, additional, Boycott, Kym, additional, Brudno, Michael, additional, Bernier, Francois, additional, van Karnebeek, Clara, additional, Kernohan, Kristin, additional, Innes, Micheil, additional, Lamont, Ryan, additional, Parboosingh, Jillian, additional, Marshall, Christian, additional, Mendoza, Roberto, additional, Dowling, James, additional, Knoppers, Bartha, additional, Lehman, Anna, additional, and Mostafavi, Sara, additional
- Published
- 2024
- Full Text
- View/download PDF
12. Monogenic variants in dystonia: an exome-wide sequencing study
- Author
-
Zech, Michael, Jech, Robert, Boesch, Sylvia, Škorvánek, Matej, Weber, Sandrina, Wagner, Matias, Zhao, Chen, Jochim, Angela, Necpál, Ján, Dincer, Yasemin, Vill, Katharina, Distelmaier, Felix, Stoklosa, Malgorzata, Krenn, Martin, Grunwald, Stephan, Bock-Bierbaum, Tobias, Fečíková, Anna, Havránková, Petra, Roth, Jan, Příhodová, Iva, Adamovičová, Miriam, Ulmanová, Olga, Bechyně, Karel, Danhofer, Pavlína, Veselý, Branislav, Haň, Vladimír, Pavelekova, Petra, Gdovinová, Zuzana, Mantel, Tobias, Meindl, Tobias, Sitzberger, Alexandra, Schröder, Sebastian, Blaschek, Astrid, Roser, Timo, Bonfert, Michaela V, Haberlandt, Edda, Plecko, Barbara, Leineweber, Birgit, Berweck, Steffen, Herberhold, Thomas, Langguth, Berthold, Švantnerová, Jana, Minár, Michal, Ramos-Rivera, Gonzalo Alonso, Wojcik, Monica H, Pajusalu, Sander, Õunap, Katrin, Schatz, Ulrich A, Pölsler, Laura, Milenkovic, Ivan, Laccone, Franco, Pilshofer, Veronika, Colombo, Roberto, Patzer, Steffi, Iuso, Arcangela, Vera, Julia, Troncoso, Monica, Fang, Fang, Prokisch, Holger, Wilbert, Friederike, Eckenweiler, Matthias, Graf, Elisabeth, Westphal, Dominik S, Riedhammer, Korbinian M, Brunet, Theresa, Alhaddad, Bader, Berutti, Riccardo, Strom, Tim M, Hecht, Martin, Baumann, Matthias, Wolf, Marc, Telegrafi, Aida, Person, Richard E, Zamora, Francisca Millan, Henderson, Lindsay B, Weise, David, Musacchio, Thomas, Volkmann, Jens, Szuto, Anna, Becker, Jessica, Cremer, Kirsten, Sycha, Thomas, Zimprich, Fritz, Kraus, Verena, Makowski, Christine, Gonzalez-Alegre, Pedro, Bardakjian, Tanya M, Ozelius, Laurie J, Vetro, Annalisa, Guerrini, Renzo, Maier, Esther, Borggraefe, Ingo, Kuster, Alice, Wortmann, Saskia B, Hackenberg, Annette, Steinfeld, Robert, Assmann, Birgit, Staufner, Christian, Opladen, Thomas, Růžička, Evžen, Cohn, Ronald D, Dyment, David, Chung, Wendy K, Engels, Hartmut, Ceballos-Baumann, Andres, Ploski, Rafal, Daumke, Oliver, Haslinger, Bernhard, Mall, Volker, Oexle, Konrad, and Winkelmann, Juliane
- Published
- 2020
- Full Text
- View/download PDF
13. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis
- Author
-
Kaneb, Hannah M, Folkmann, Andrew W, Belzil, Véronique V, Jao, Li-En, Leblond, Claire S, Girard, Simon L, Daoud, Hussein, Noreau, Anne, Rochefort, Daniel, Hince, Pascale, Szuto, Anna, Levert, Annie, Vidal, Sabrina, André-Guimont, Catherine, Camu, William, Bouchard, Jean-Pierre, Dupré, Nicolas, Rouleau, Guy A, Wente, Susan R, and Dion, Patrick A
- Subjects
Biochemistry and Cell Biology ,Bioinformatics and Computational Biology ,Genetics ,Biological Sciences ,Rare Diseases ,Neurosciences ,Brain Disorders ,ALS ,Neurodegenerative ,Orphan Drug ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Amyotrophic Lateral Sclerosis ,Animals ,Arthrogryposis ,Codon ,Nonsense ,DNA-Binding Proteins ,Disease Models ,Animal ,Haploinsufficiency ,HeLa Cells ,Humans ,Microscopy ,Confocal ,Motor Neurons ,Mutation ,Missense ,Nuclear Pore ,Nucleocytoplasmic Transport Proteins ,Pedigree ,Protein Processing ,Post-Translational ,RNA Splicing ,RNA ,Messenger ,Zebrafish ,Hela Cells ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.
- Published
- 2015
14. Protocol for a Prospective, Observational Cost-effectiveness Analysis of Returning Secondary Findings of Genome Sequencing for Unexplained Suspected Genetic Conditions
- Author
-
Ungar, Wendy J., primary, Hayeems, Robin Z., additional, Marshall, Christian R., additional, Gillespie, Meredith K., additional, Szuto, Anna, additional, Chisholm, Caitlin, additional, James Stavropoulos, D., additional, Huang, Lijia, additional, Jarinova, Olga, additional, Wu, Vercancy, additional, Tsiplova, Kate, additional, Lau, Lynnette, additional, Lee, Whiwon, additional, Venkataramanan, Viji, additional, Sawyer, Sarah, additional, Mendoza-Londono, Roberto, additional, Somerville, Martin J., additional, and Boycott, Kym M., additional
- Published
- 2023
- Full Text
- View/download PDF
15. P873: “If you look for a problem, you’ll find one”: A qualitative study to understand why parents/adult patients decline secondary findings
- Author
-
Hansen, Abigail, Luca, Stephanie, Moran, Olivia, Babul-Hirji, Riyana, Yan, Joyce, Fooks, Katharine, Venkataramanan, Viji, Ungar, Wendy, Hayeems, Robin, Study Team, Secondary Findings, Poole, Elise, Assamad, Daniel, Banglorewala, Pooja, Vermeer, Lydia, Marshall, Christian, Gillespie, Meredith, Szuto, Anna, Chisholm, Caitlin, Stavropoulos, James, Huang, Lijia, Jarinova, Olga, Lau, Lynette, Lee, Whiwon, Badalato, Lauren, Balci, Tugce, Chad, Lauren, Inglese, Cara, Ladouceur, Virginie, Mackley, Michael, Morel, Chantal, Richer, Julie, Tarnopolsky, Mark, Villani, Anita, Zahavich, Laura, Sawyer, Sarah, Mendoza-Londono, Roberto, Somerville, Martin, and Boycott, Kym
- Published
- 2024
- Full Text
- View/download PDF
16. P866: Exploring the impact of secondary findings in a cohort of patients and families receiving genome-wide sequencing
- Author
-
Fooks, Katharine, Vermeer, Lydia, Poole, Elise, Luca, Stephanie, Babul-Hirji, Riyana, Chad, Lauren, Chitayat, David, Mackley, Michael, Schwartz, Marci, Ungar, Wendy, Hayeems, Robin, Study Team, Secondary Findings, Yan, Joyce, Hansen, Abigail, Venkataramanan, Viji, Assamad, Daniel, Marshall, Christian, Gillespie, Meredith, Szuto, Anna, Chisholm, Caitlin, Stavropoulos, James, Huang, Lijia, Jarinova, Olga, Lau, Lynette, Lee, Whiwon, Badalato, Lauren, Balci, Tugce, Inglese, Cara, Ladouceur, Virginie Beausejour, Morel, Chantal, Richer, Julie, Tarnopolsky, Mark, Villani, Anita, Zahavich, Laura, Moran, Olivia, Sawyer, Sarah, Mendoza-Londono, Roberto, Somerville, Martin, and Boycott, Kym
- Published
- 2024
- Full Text
- View/download PDF
17. P642: Development and deployment of clinical genome sequencing using a cloud-based platform
- Author
-
Lau, Lynette, Higginbotham, Edward, Sung, Wilson, Sriretnakumar, Venuja, Curtis, Meredith, Chisholm, Caitlin, Gillespie, Meredith, Pan, Anna, Kim, Sean, Simko, Sean, Price, E. Magda, Eliou, Marianne, Szuto, Anna, Axford, Michelle, Somerville, Martin, Boycott, Kym, McGowan-Jordan, Jean, Bergeron, Melaine Beaulieu, Stavropoulos, James, Huang, Lijia, and Marshall, Christian
- Published
- 2024
- Full Text
- View/download PDF
18. P616: Genome-wide Sequencing Ontario (GSO): Insight into Ontario’s rare disease landscape
- Author
-
Gillespie, Meredith, Hayeems, Robin, Marshall, Christian, Szuto, Anna, Chisholm, Caitlin, Ungar, Wendy, Stavropoulos, James, Huang, Lijia, Venkataramanan, Viji, Lau, Lynette, Sung, Wilson, Bergeron, Melanie Beaulieu, Higginbotham, Ted, Curtis, Meredith, Sriretnakumar, Venuja, Zaidi, Hassan, Hitchcock, Emma, Schaffer, Audrey, Sawyer, Sarah, Costain, Gregory, Mendoza-Londono, Roberto, Somerville, Martin, Boycott, Kym, and Hartley, Taila
- Published
- 2024
- Full Text
- View/download PDF
19. P597: All for One Clinical Genomics Network: Linking Canadian diagnostic laboratories to share genome-wide sequencing data to support rare disease diagnosis
- Author
-
Price, E. Magda, Gillespie, Meredith, Chisholm, Caitlin, Attali, Ruben, Silver, Talia, Szuto, Anna, Team, GSO Study, Michaud, Jacques, Bulman, Dennis, Lerner-Ellis, Jordan, Zawati, Ma'n, Ferretti, Vincent, Bernier, Francois, Marshall, Christian, and Boycott, Kym
- Published
- 2024
- Full Text
- View/download PDF
20. P540: Genome-wide Sequencing Ontario (GSO): Canada’s first provincial clinical genome-wide sequencing service
- Author
-
Gillespie, Meredith, Hayeems, Robin, Marshall, Christian, Szuto, Anna, Chisholm, Caitlin, Stavropoulos, James, Huang, Lijia, Lau, Lynette, Sung, Wilson, Bergeron, Melanie Beaulieu, Higginbotham, Ted, Curtis, Meredith, Sriretnakumar, Venuja, Zaidi, Hassan, Hitchcock, Emma, Schaffer, Audrey, Hartley, Taila, Sawyer, Sarah, Ungar, Wendy, Costain, Gregory, Mendoza-Londono, Roberto, Pan, Anna, Keating, Jennifer, Matviychuk, Diana, Braid, Tamara, Carroll, Niri, Somerville, Martin, and Boycott, Kym
- Published
- 2024
- Full Text
- View/download PDF
21. O05: A micro-costing and cost-effectiveness analysis of genome sequencing vs exome sequencing in pediatric rare diseases
- Author
-
Ungar, Wendy, Wu, Vercancy, Marshall, Christian, Hwang, Jackie, Hayeems, Robin, Tsiplova, Kate, Gillespie, Meredith, Szuto, Anna, Chisholm, Caitlin, Stavropoulos, Dimitri, Venkataramanan, Viji, Xiao, Bowen, Li, Sheena, Costain, Gregory, Bergeron, Melanie Beaulieu, Sawyer, Sarah, Lau, Lynette, Huang, Lijia, Mendoza-Londono, Roberto, Smith, Brian, Higginbotham, Edward, Somerville, Martin, and Boycott, Kym
- Published
- 2024
- Full Text
- View/download PDF
22. P388: Noonan syndrome associated with a homozygous deep intronic variant in LZTR1 gene confirmed by RNA sequencing
- Author
-
Dupuis, Lucie, Szuto, Anna, Marshall, Christian, Kyriakopoulou, Lianna, Mendoza-Londono, Roberto, and McNiven, Vanda
- Published
- 2024
- Full Text
- View/download PDF
23. A 23 years follow-up study identifies GLUT1 deficiency syndrome initially diagnosed as complicated hereditary spastic paraplegia
- Author
-
Diomedi, Marina, Gan-Or, Ziv, Placidi, Fabio, Dion, Patrick A., Szuto, Anna, Bengala, Mario, Rouleau, Guy A., and Gigli, Gian Luigi
- Published
- 2016
- Full Text
- View/download PDF
24. jamaneurology_morton_2022_rv_220001_1646244188.29201.pdf
- Author
-
Morton, Sarah U, Christodoulou, John, Costain, Gregory, Muntoni, Francesco, Wakeling, Emma, Wojcik, Monica, French, Courtney E., Szuto, Anna, Dowling, James J., D. Cohn, Ronald, Raymond, F. Lucy, T. Darras, Basil, A. Williams, David, Lunke, Sebastian, Stark, Zornitza, Rowitch, David H., and B. Agrawal, Pankaj
- Subjects
Infant and child health ,Neonatology - Abstract
IMPORTANCE Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease. OBSERVATIONS The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations. CONCLUSIONS AND RELEVANCE This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice.
- Published
- 2023
- Full Text
- View/download PDF
25. Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data
- Author
-
Taila, Hartley, Élisabeth, Soubry, Meryl, Acker, Matthew, Osmond, Madeline, Couse, Meredith K, Gillespie, Yoko, Ito, Aren E, Marshall, Gabrielle, Lemire, Lijia, Huang, Caitlin, Chisholm, Alison J, Eaton, E Magda, Price, James J, Dowling, Arun K, Ramani, Roberto, Mendoza-Londono, Gregory, Costain, Michelle M, Axford, Anna, Szuto, Vanda, McNiven, Nadirah, Damseh, Rebekah, Jobling, Leanne, de Kock, Bahareh A, Mojarad, Ted, Young, Zhuo, Shao, Robin Z, Hayeems, Ian D, Graham, Mark, Tarnopolsky, Lauren, Brady, Christine M, Armour, Michael, Geraghty, Julie, Richer, Sarah, Sawyer, Matthew, Lines, Saadet, Mercimek-Andrews, Melissa T, Carter, Gail, Graham, Peter, Kannu, Joanna, Lazier, Chumei, Li, Ritu B, Aul, Tugce B, Balci, Nomazulu, Dlamini, Lauren, Badalato, Andrea, Guerin, Jagdeep, Walia, David, Chitayat, Ronald, Cohn, Hanna, Faghfoury, Cynthia, Forster-Gibson, Hernan, Gonorazky, Eyal, Grunebaum, Michal, Inbar-Feigenberg, Natalya, Karp, Chantal, Morel, Alison, Rusnak, Neal, Sondheimer, Jodi, Warman-Chardon, Priya T, Bhola, Danielle K, Bourque, Inara J, Chacon, Lauren, Chad, Pranesh, Chakraborty, Karen, Chong, Asif, Doja, Elaine Suk-Ying, Goh, Maha, Saleh, Beth K, Potter, Christian R, Marshall, David A, Dyment, Kristin, Kernohan, and Kym M, Boycott
- Subjects
Genetics ,Genetics (clinical) - Abstract
We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses.
- Published
- 2022
26. Rapid Genetic Testing in Pediatric and Neonatal Critical Care: A Scoping Review of Emerging Ethical Issues
- Author
-
Lauren Chad, James Anderson, Diana Cagliero, Robin Z. Hayeems, Linh G. Ly, and Anna Szuto
- Subjects
Critical Care ,Pediatrics, Perinatology and Child Health ,Beneficence ,Infant, Newborn ,Humans ,General Medicine ,Genetic Testing ,Child ,Pediatrics ,Resource Allocation - Abstract
BACKGROUND Rapid genome-wide sequencing (rGWS) is being increasingly used to aid in prognostication and decision-making for critically ill newborns and children. Although its feasibility in this fast-paced setting has been described, this new paradigm of inpatient genetic care raises new ethical challenges. OBJECTIVE A scoping review was performed to (1) identify salient ethical issues in this area of practice; and (2) bring attention to gaps and ethical tensions that warrant more deliberate exploration. METHODS Data sources, Ovid Medline and Cochrane Central Register of Controlled Trials, were searched up to November 2021. Articles included were those in English relating to rGWS deployed rapidly in a critical care setting. Publications were examined for ethical themes and were further characterized as including a superficial or in-depth discussion of that theme. New themes were inductively identified as they emerged. RESULTS Ninety-nine studies, published in 2012 or thereafter, met inclusion criteria. Themes identified elaborated upon established ethical principles related to beneficence and nonmaleficence (ie, clinical utility, medical uncertainty, impact on family, and data security) autonomy (ie, informed consent), and justice (ie, resource allocation and disability rights). Many themes were only narrowly discussed. CONCLUSIONS The application of rGWS in neonatal and pediatric acute care is inherently tied to ethically charged issues, some of which are reported here. Attention to the ethical costs and benefits of rGWS is not always discussed, with important gaps and unanswered questions that call for ongoing focus on these ethical considerations in this next application of acute care genomics.
- Published
- 2022
27. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change
- Author
-
Heidi L Rehm, Joseph T Alaimo, Swaroop Aradhya, Pinar Bayrak-Toydemir, Hunter Best, Rhonda Brandon, Jillian G Buchan, Elizabeth C Chao, Elaine Chen, Jacob Clifford, Ana S Cohen, Laura K Conlin, Soma Das, Kyle W Davis, Daniela del Gaudio, Florencia Del Viso, Christina DiVincenzo, Marcia Eisenberg, Lucia Guidugli, Monia B Hammer, Steven M Harrison, Kathryn E Hatchell, Lindsay Havens Dyer, Lily U Hoang, James M Holt, Vaidehi Jobanputra, Izabela D Karbassi, Hutton M Kearney, Melissa A Kelly, Jacob M Kelly, Michelle L Kluge, Timothy Komala, Paul Kruszka, Lynette Lau, Matthew S Lebo, Christian R Marshall, Dianalee McKnight, Kirsty McWalter, Yan Meng, Narasimhan Nagan, Christian S Neckelmann, Nir Neerman, Zhiyv Niu, Vitoria K Paolillo, Sarah A Paolucci, Denise Perry, Tina Pesaran, Kelly Radtke, Kristen J Rasmussen, Kyle Retterer, Carol J Saunders, Elizabeth Spiteri, Christine M Stanley, Anna Szuto, Ryan J Taft, Isabelle Thiffault, Brittany C Thomas, Amanda Thomas-Wilson, Erin Thorpe, Timothy J Tidwell, Meghan C Towne, and Hana Zouk
- Abstract
Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact. We collected data from over 1.5 million genetic tests from 19 clinical laboratories across the United States and Canada from during 2020-2021. We found a lower rate of inconclusive results due to VUS on ES/GS tests compared to MGPs (22.5% vs. 32.6%; p
- Published
- 2022
28. Rapid Genetic Testing in Pediatric and Neonatal Critical Care: A Scoping Review of Emerging Ethical Issues
- Author
-
Chad, Lauren, primary, Anderson, James, additional, Cagliero, Diana, additional, Hayeems, Robin Z., additional, Ly, Linh G., additional, and Szuto, Anna, additional
- Published
- 2022
- Full Text
- View/download PDF
29. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change
- Author
-
Rehm, Heidi L, primary, Alaimo, Joseph T, additional, Aradhya, Swaroop, additional, Bayrak-Toydemir, Pinar, additional, Best, Hunter, additional, Brandon, Rhonda, additional, Buchan, Jillian G, additional, Chao, Elizabeth C, additional, Chen, Elaine, additional, Clifford, Jacob, additional, Cohen, Ana S, additional, Conlin, Laura K, additional, Das, Soma, additional, Davis, Kyle W, additional, Gaudio, Daniela del, additional, Viso, Florencia Del, additional, DiVincenzo, Christina, additional, Eisenberg, Marcia, additional, Guidugli, Lucia, additional, Hammer, Monia B, additional, Harrison, Steven M, additional, Hatchell, Kathryn E, additional, Dyer, Lindsay Havens, additional, Hoang, Lily U, additional, Holt, James M, additional, Jobanputra, Vaidehi, additional, Karbassi, Izabela D, additional, Kearney, Hutton M, additional, Kelly, Melissa A, additional, Kelly, Jacob M, additional, Kluge, Michelle L, additional, Komala, Timothy, additional, Kruszka, Paul, additional, Lau, Lynette, additional, Lebo, Matthew S, additional, Marshall, Christian R, additional, McKnight, Dianalee, additional, McWalter, Kirsty, additional, Meng, Yan, additional, Nagan, Narasimhan, additional, Neckelmann, Christian S, additional, Neerman, Nir, additional, Niu, Zhiyv, additional, Paolillo, Vitoria K, additional, Paolucci, Sarah A, additional, Perry, Denise, additional, Pesaran, Tina, additional, Radtke, Kelly, additional, Rasmussen, Kristen J, additional, Retterer, Kyle, additional, Saunders, Carol J, additional, Spiteri, Elizabeth, additional, Stanley, Christine M, additional, Szuto, Anna, additional, Taft, Ryan J, additional, Thiffault, Isabelle, additional, Thomas, Brittany C, additional, Thomas-Wilson, Amanda, additional, Thorpe, Erin, additional, Tidwell, Timothy J, additional, Towne, Meghan C, additional, and Zouk, Hana, additional
- Published
- 2022
- Full Text
- View/download PDF
30. Clinical and genetic study of hereditary spastic paraplegia in Canada
- Author
-
Chrestian, Nicolas, Dupré, Nicolas, Gan-Or, Ziv, Szuto, Anna, Chen, Shiyi, Venkitachalam, Anil, Brisson, Jean-Denis, Warman-Chardon, Jodi, Ahmed, Sohnee, Ashtiani, Setareh, MacDonald, Heather, Mohsin, Noreen, Mourabit-Amari, Karim, Provencher, Pierre, Boycott, Kym M., Stavropoulos, Dimitri J., Dion, Patrick A., Ray, Peter N., Suchowersky, Oksana, Rouleau, Guy A., and Yoon, Grace
- Published
- 2017
- Full Text
- View/download PDF
31. Comparing genome sequencing technologies to improve rare disease diagnostics: a protocol for the evaluation of a pilot project, Genome-wide Sequencing Ontario
- Author
-
Robin Z. Hayeems, Christian R. Marshall, Meredith K. Gillespie, Anna Szuto, Caitlin Chisholm, Dimitri J. Stavropoulos, Viji Venkataramanan, Kate Tsiplova, Sarah Sawyer, E. Magda Price, Lynette Lau, Reem Khan, Whiwon Lee, Lijia Huang, Olga Jarinova, Wendy J. Ungar, Roberto Mendoza-Londono, Martin J. Somerville, and Kym M. Boycott
- Subjects
Ontario ,Rare Diseases ,Exome Sequencing ,Humans ,Pilot Projects ,General Medicine ,Prospective Studies ,Child ,Randomized Controlled Trials as Topic - Abstract
Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada.The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa. Enrolment of a prospective cohort of patients began on Apr. 1, 2021. Eligible cases with blood samples available for the index case and both parents (i.e., trios) are randomized to receive exome sequencing or genome sequencing. We will collect patient-level data and ascertain costs associated with the laboratory workflow for exome sequencing and genome sequencing. We will compare point estimates for the diagnostic utility and timeliness of exome sequencing and genome sequencing, and we will determine an incremental cost-effectiveness ratio (expressed as the incremental cost of genome sequencing versus exome sequencing per additional patient with a causal variant detected).Findings from this work will provide robust evidence for the diagnostic utility, cost-effectiveness and timeliness of exome sequencing and genome sequencing, and will be disseminated via academic publications and policy briefs. Findings will inform provincial and cross-provincial policy related to the long-term organization, delivery and reimbursement of clinical-grade genome diagnostics for rare disease.
- Published
- 2022
32. Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review
- Author
-
Sarah U. Morton, John Christodoulou, Gregory Costain, Francesco Muntoni, Emma Wakeling, Monica H. Wojcik, Courtney E. French, Anna Szuto, James J. Dowling, Ronald D. Cohn, F. Lucy Raymond, Basil T. Darras, David A. Williams, Sebastian Lunke, Zornitza Stark, David H. Rowitch, and Pankaj B. Agrawal
- Subjects
Consensus ,Intensive Care Units, Neonatal ,Exome Sequencing ,Infant, Newborn ,Humans ,Infant ,Multicenter Studies as Topic ,Muscle Hypotonia ,Neurology (clinical) ,Genetic Testing ,Child ,Article - Abstract
IMPORTANCE: Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease. OBSERVATIONS: The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations. CONCLUSIONS AND RELEVANCE: This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice.
- Published
- 2022
33. Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review
- Author
-
Morton, Sarah U., primary, Christodoulou, John, additional, Costain, Gregory, additional, Muntoni, Francesco, additional, Wakeling, Emma, additional, Wojcik, Monica H., additional, French, Courtney E., additional, Szuto, Anna, additional, Dowling, James J., additional, Cohn, Ronald D., additional, Raymond, F. Lucy, additional, Darras, Basil T., additional, Williams, David A., additional, Lunke, Sebastian, additional, Stark, Zornitza, additional, Rowitch, David H., additional, and Agrawal, Pankaj B., additional
- Published
- 2022
- Full Text
- View/download PDF
34. Comparing genome sequencing technologies to improve rare disease diagnostics: a protocol for the evaluation of a pilot project, Genome-wide Sequencing Ontario
- Author
-
Hayeems, Robin Z., primary, Marshall, Christian R., additional, Gillespie, Meredith K., additional, Szuto, Anna, additional, Chisholm, Caitlin, additional, Stavropoulos, Dimitri J., additional, Venkataramanan, Viji, additional, Tsiplova, Kate, additional, Sawyer, Sarah, additional, Price, E. Magda, additional, Lau, Lynette, additional, Khan, Reem, additional, Lee, Whiwon, additional, Huang, Lijia, additional, Jarinova, Olga, additional, Ungar, Wendy J., additional, Mendoza-Londono, Roberto, additional, Somerville, Martin J., additional, and Boycott, Kym M., additional
- Published
- 2022
- Full Text
- View/download PDF
35. Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data.
- Author
-
Hartley, Taila, Soubry, Élisabeth, Acker, Meryl, Osmond, Matthew, Couse, Madeline, Gillespie, Meredith K., Ito, Yoko, Marshall, Aren E., Lemire, Gabrielle, Huang, Lijia, Chisholm, Caitlin, Eaton, Alison J., Price, E. Magda, Dowling, James J., Ramani, Arun K., Mendoza‐Londono, Roberto, Costain, Gregory, Axford, Michelle M., Szuto, Anna, and McNiven, Vanda
- Subjects
MEDICAL research ,CLINICAL medicine ,DIAGNOSIS ,TRANSLATIONAL research ,PATHOLOGICAL laboratories - Abstract
We examined the utility of clinical and research processes in the reanalysis of publicly‐funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically‐relevant genes is modest, and the highest yield comes from validation of novel disease‐gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
36. eP500: Genome-wide Sequencing Ontario (GSO): An implementation pilot to improve rare disease diagnostics
- Author
-
Marshall, Christian, primary, Gillespie, Meredith, additional, Szuto, Anna, additional, Chisholm, Caitlin, additional, Stavropoulos, James, additional, Venkataramanan, Viji, additional, Tsiplova, Kate, additional, Price, Magda, additional, Lau, Lynette, additional, Khan, Reem, additional, Lee, Whiwon, additional, Huang, Lijia, additional, Jarinova, Olga, additional, Sawyer, Sarah, additional, Ungar, Wendy, additional, Mendoza, Roberto, additional, Hayeems, Robin, additional, Somerville, Martin, additional, and Boycott, Kym, additional
- Published
- 2022
- Full Text
- View/download PDF
37. eP500: Genome-wide Sequencing Ontario (GSO): An implementation pilot to improve rare disease diagnostics
- Author
-
Christian Marshall, Meredith Gillespie, Anna Szuto, Caitlin Chisholm, James Stavropoulos, Viji Venkataramanan, Kate Tsiplova, Magda Price, Lynette Lau, Reem Khan, Whiwon Lee, Lijia Huang, Olga Jarinova, Sarah Sawyer, Wendy Ungar, Roberto Mendoza, Robin Hayeems, Martin Somerville, and Kym Boycott
- Subjects
Genetics (clinical) - Published
- 2022
38. SYNE1 Mutations in Autosomal Recessive Cerebellar Ataxia
- Author
-
Noreau, Anne, Bourassa, Cynthia V., Szuto, Anna, Levert, Annie, Dobrzeniecka, Sylvia, Gauthier, Julie, Forlani, Sylvie, Durr, Alexandra, Anheim, Mathieu, Stevanin, Giovanni, Brice, Alexis, Bouchard, Jean-Pierre, Dion, Patrick A., Dupré, Nicolas, and Rouleau, Guy A.
- Published
- 2013
- Full Text
- View/download PDF
39. Monogenic variants in dystonia: an exome-wide sequencing study
- Author
-
Gonzalo Alonso Ramos-Rivera, Julia Vera, Holger Prokisch, Sebastian Schröder, Michal Minár, Hartmut Engels, Thomas Herberhold, Jessica Becker, Robert Jech, Anna Szuto, Angela Jochim, Theresa Brunet, Tobias Meindl, V. Kraus, Ivan Milenkovic, Alexandra Sitzberger, Jana Švantnerová, Birgit Assmann, Evžen Růžička, Felix Distelmaier, Chen Zhao, Martin Krenn, Stephan Grunwald, Renzo Guerrini, Christine Makowski, Alice Kuster, Yasemin Dincer, Pedro Gonzalez-Alegre, Petra Havránková, Bader Alhaddad, Zuzana Gdovinova, Tobias Bock-Bierbaum, Annette Hackenberg, Friederike Wilbert, Esther M. Maier, Katrin Õunap, Francisca Millan Zamora, David Weise, Birgit Leineweber, Vladimír Haň, Matias Wagner, Roberto Colombo, Marc E. Wolf, Tim M. Strom, Laura Pölsler, Veronika Pilshofer, Tanya Bardakjian, Steffi Patzer, Oliver Daumke, Ingo Borggraefe, Korbinian M. Riedhammer, Richard E. Person, Ulrich A. Schatz, Michaela Bonfert, Jan Roth, Monica H. Wojcik, Riccardo Berutti, Wendy K. Chung, Robert Steinfeld, Kirsten Cremer, Sylvia Boesch, Steffen Berweck, Ján Necpál, Berthold Langguth, Matej Skorvanek, Mónica Troncoso, Fang Fang, Laurie J. Ozelius, Dominik S. Westphal, Bernhard Haslinger, Rafał Płoski, Jens Volkmann, Konrad Oexle, Thomas Musacchio, Martin Hecht, Aida Telegrafi, Matthias Eckenweiler, Edda Haberlandt, Arcangela Iuso, Volker Mall, Michael Zech, Christian Staufner, Thomas Opladen, Sander Pajusalu, Lindsay B. Henderson, Thomas Sycha, Karel Bechyně, Petra Pavelekova, David A. Dyment, Iva Příhodová, Katharina Vill, Annalisa Vetro, Tobias Mantel, Malgorzata Stoklosa, Miriam Adamovičová, Anna Fečíková, Fritz Zimprich, Pavlína Danhofer, Juliane Winkelmann, Franco Laccone, Elisabeth Graf, Sandrina Weber, Timo Roser, Saskia B. Wortmann, Astrid Blaschek, Ronald D. Cohn, Olga Ulmanová, Andres O. Ceballos-Baumann, Matthias Baumann, Branislav Veselý, and Barbara Plecko
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Pediatrics ,Movement disorders ,Adolescent ,Context (language use) ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Exome Sequencing ,medicine ,Humans ,Exome ,Child ,Exome sequencing ,Dystonia ,business.industry ,Genetic heterogeneity ,Infant, Newborn ,Genetic Variation ,Infant ,medicine.disease ,3. Good health ,Pedigree ,030104 developmental biology ,Child, Preschool ,Medical genetics ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Dystonic disorder - Abstract
Summary Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. Funding Else Kroner-Fresenius-Stiftung, Technische Universitat Munchen, Helmholtz Zentrum Munchen, Medizinische Universitat Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
- Published
- 2020
40. Insensitivity to Pain: Lessons from Recent Genetics Advances
- Author
-
Merner, Nancy, primary, Dion, Patrick A., additional, Szuto, Anna, additional, and Rouleau, Guy A., additional
- Published
- 2012
- Full Text
- View/download PDF
41. C9orf72 Hexanucleotide Repeat Expansions as the Causative Mutation for Chromosome 9p21–Linked Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
- Author
-
Daoud, Hussein, Suhail, Hamid, Sabbagh, Mike, Belzil, Veronique, Szuto, Anna, Dionne-Laporte, Alexandre, Khoris, Jawad, Camu, William, Salachas, Francois, Meininger, Vincent, Mathieu, Jean, Strong, Michael, Dion, Patrick A., and Rouleau, Guy A.
- Published
- 2012
- Full Text
- View/download PDF
42. An 18 Alanine Repeat in a Severe Form of Oculopharyngeal Muscular Dystrophy
- Author
-
Patrick A. Dion, E. Carney, Guy A. Rouleau, K. David, D. Rocheford, L. Jouan, and Anna Szuto
- Subjects
Alanine ,Pathology ,medicine.medical_specialty ,General Medicine ,Middle Aged ,Biology ,medicine.disease ,Severity of Illness Index ,Pedigree ,Oculopharyngeal muscular dystrophy ,Muscular Dystrophy, Oculopharyngeal ,Neurology ,medicine ,Humans ,Female ,Neurology (clinical) ,Trinucleotide Repeat Expansion - Published
- 2014
43. A 23 years follow-up study identifies GLUT1 deficiency syndrome initially diagnosed as complicated hereditary spastic paraplegia
- Author
-
Patrick A. Dion, Guy A. Rouleau, Gian Luigi Gigli, Fabio Placidi, Mario Bengala, Anna Szuto, Ziv Gan-Or, and Marina Diomedi
- Subjects
0301 basic medicine ,Male ,Pediatrics ,Genetic Linkage ,GLUT1 deficiency syndrome ,Hereditary spastic paraplegia ,Epilepsy ,0302 clinical medicine ,Intellectual disability ,Spastic ,Medicine ,Spastic Paraplegia ,Exome ,Child ,Exome sequencing ,Genetics (clinical) ,Glucose Transporter Type 1 ,Inborn Errors ,Autosomal dominant trait ,High-Throughput Nucleotide Sequencing ,General Medicine ,Phenotype ,Hereditary ,Italy ,Child, Preschool ,SLC2A1 ,Spasticity ,Adolescent ,Adult ,Carbohydrate Metabolism, Inborn Errors ,Female ,Humans ,Infant ,Infant, Newborn ,Monosaccharide Transport Proteins ,Spastic Paraplegia, Hereditary ,Genetics ,Carbohydrate Metabolism ,Settore MED/26 - Neurologia ,Paraplegia ,medicine.medical_specialty ,03 medical and health sciences ,Preschool ,business.industry ,medicine.disease ,Newborn ,030104 developmental biology ,Settore MED/03 - Genetica Medica ,business ,030217 neurology & neurosurgery ,Rare disease - Abstract
Glucose transporter 1 (GLUT1) deficiency syndrome (GLUT1DS) was initially described in the early 90s as a sporadic clinical condition, characterized by seizures, motor and intellectual impairment with variable clinical presentation, and without a known genetic cause. Although causative mutations in SLC2A1 were later identified and much more is known about the disease, it still remains largely underdiagnosed. In the current study, a previously described Italian family was re-analyzed using whole exome sequencing and clinically re-evaluated. Affected individuals presented with spastic paraplegia as a predominant symptom, with epilepsy and intellectual disability, inherited as an autosomal dominant trait with variable clinical presentation. While a novel variant of hereditary spastic paraplegia (HSP) was initially hypothesized in this family, previous linkage studies of known HSP genes did not identify the genetic cause. Exome-sequencing study identified a p.Arg126Cys mutation in the SLC2A1 gene, encoding GLUT1, which segregated with the affected members of the family. The diagnosis of GLUT1DS was further confirmed by cerebrospinal fluid analysis, and treatment was started with good initial response. The description of this large family provides further clinical information on this rare disease. It also offers an example of how GLUT1DS can be challenging to diagnose, and emphasizes the importance of lumbar puncture in the workflow of similar syndromes. Finally, it suggests that analysis of SLC2A1 should be considered in the diagnostic work up of HSP, especially if it is associated with epilepsy.
- Published
- 2016
44. Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum
- Author
-
Patrick A. Dion, Daniel Rochefort, Hugo Théoret, Maryse Lassonde, Sylvia Dobrzeniecka, Loubna Jouan, Alexandre Dionne-Laporte, Pascale Hince, Guy A. Rouleau, Bouchra Ouled Amar Bencheikh, Dan Spiegelman, Anna Szuto, Marine Barbelanne, Hussein Daoud, and William Y. Tsang
- Subjects
0301 basic medicine ,Adult ,Male ,Heterozygote ,Short Report ,Mutation, Missense ,Cell Cycle Proteins ,Nerve Tissue Proteins ,Biology ,Corpus callosum ,Compound heterozygosity ,Bioinformatics ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Exome ,Agenesis of the corpus callosum ,Gene ,Genetics (clinical) ,Exome sequencing ,CDK5RAP2 ,Siblings ,Intracellular Signaling Peptides and Proteins ,Middle Aged ,medicine.disease ,030104 developmental biology ,nervous system ,Agenesis ,Female ,Agenesis of Corpus Callosum ,030217 neurology & neurosurgery - Abstract
Agenesis of the corpus callosum (ACC) is a common brain malformation which can be observed either as an isolated condition or as part of numerous congenital syndromes. Therefore, cognitive and neurological involvements in patients with ACC are variable, from mild linguistic and behavioral impairments to more severe neurological deficits. To date, the underlying genetic causes of isolated ACC remains elusive and causative genes have yet to be identified. We performed exome sequencing on three acallosal siblings from the same non-consanguineous family and identified compound heterozygous variants, p.[Gly94Arg];[Asn1232Ser], in the protein encoded by the CDK5RAP2 gene, also known as MCPH3, a gene previously reported to cause autosomal recessive primary microcephaly. Our findings suggest a novel role for this gene in the pathogenesis of isolated ACC.
- Published
- 2015
45. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis
- Author
-
Patrick A. Dion, Daniel Rochefort, Veronique V. Belzil, Pascale Hince, Catherine André-Guimont, Andrew W. Folkmann, Annie Levert, Susan R. Wente, Hannah M. Kaneb, Guy A. Rouleau, Anne Noreau, Hussein Daoud, William Camu, Sabrina Vidal, Li-En Jao, Anna Szuto, Jean-Pierre Bouchard, Claire S. Leblond, Nicolas Dupré, Simon Girard, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Nucleocytoplasmic Transport Proteins ,Messenger ,Haploinsufficiency ,Neurodegenerative ,medicine.disease_cause ,Medical and Health Sciences ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Missense mutation ,Aetiology ,Amyotrophic lateral sclerosis ,Zebrafish ,Genetics (clinical) ,Genetics & Heredity ,Genetics ,Arthrogryposis ,Motor Neurons ,Microscopy ,0303 health sciences ,Mutation ,Microscopy, Confocal ,biology ,General Medicine ,Articles ,Biological Sciences ,3. Good health ,Pedigree ,DNA-Binding Proteins ,Codon, Nonsense ,Confocal ,Neurological ,Lethal arthrogryposis with anterior horn cell disease ,RNA Splicing ,Nonsense mutation ,Mutation, Missense ,03 medical and health sciences ,Rare Diseases ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,RNA, Messenger ,Codon ,Molecular Biology ,Protein Processing ,030304 developmental biology ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Animal ,Lethal congenital contracture syndrome ,Amyotrophic Lateral Sclerosis ,Post-Translational ,Neurosciences ,biology.organism_classification ,medicine.disease ,Brain Disorders ,Disease Models, Animal ,Orphan Drug ,Nonsense ,Hela Cells ,Disease Models ,Nuclear Pore ,RNA ,Missense ,ALS ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
International audience; Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.
- Published
- 2015
46. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change
- Author
-
Rehm, Heidi L., Alaimo, Joseph T., Aradhya, Swaroop, Bayrak-Toydemir, Pinar, Best, Hunter, Brandon, Rhonda, Buchan, Jillian G., Chao, Elizabeth C., Chen, Elaine, Clifford, Jacob, Cohen, Ana S.A., Conlin, Laura K., Das, Soma, Davis, Kyle W., del Gaudio, Daniela, Del Viso, Florencia, DiVincenzo, Christina, Eisenberg, Marcia, Guidugli, Lucia, Hammer, Monia B., Harrison, Steven M., Hatchell, Kathryn E., Dyer, Lindsay Havens, Hoang, Lily U., Holt, James M., Jobanputra, Vaidehi, Karbassi, Izabela D., Kearney, Hutton M., Kelly, Melissa A., Kelly, Jacob M., Kluge, Michelle L., Komala, Timothy, Kruszka, Paul, Lau, Lynette, Lebo, Matthew S., Marshall, Christian R., McKnight, Dianalee, McWalter, Kirsty, Meng, Yan, Nagan, Narasimhan, Neckelmann, Christian S., Neerman, Nir, Niu, Zhiyv, Paolillo, Vitoria K., Paolucci, Sarah A., Perry, Denise, Pesaran, Tina, Radtke, Kelly, Rasmussen, Kristen J., Retterer, Kyle, Saunders, Carol J., Spiteri, Elizabeth, Stanley, Christine, Szuto, Anna, Taft, Ryan J., Thiffault, Isabelle, Thomas, Brittany C., Thomas-Wilson, Amanda, Thorpe, Erin, Tidwell, Timothy J., Towne, Meghan C., Zouk, Hana, Marshall, Christian, Meng, Linyan, Jobanputra, Vaidehi, Taft, Ryan, Ashley, Euan, Nakouzi, Ghunwa, Shen, Wei, Kingsmore, Stephen, and Rehm, Heidi
- Abstract
Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.
- Published
- 2023
- Full Text
- View/download PDF
47. Chromosomal Position Effects Are Linked to Sir2-Mediated Variation in Transcriptional Burst Size
- Author
-
Anna Szuto, John C. Bell, Mads Kærn, Cory Batenchuk, Kristin Baetz, Lioudmila Tepliakova, Samyuktha Adiga, Simon St-Pierre, and Nazir Kabbani
- Subjects
Transcription, Genetic ,Biophysics ,Saccharomyces cerevisiae ,Biology ,Chromosomal Position Effects ,03 medical and health sciences ,Sirtuin 2 ,0302 clinical medicine ,Gene Expression Regulation, Fungal ,mental disorders ,Gene expression ,Silent Information Regulator Proteins, Saccharomyces cerevisiae ,030304 developmental biology ,Genetics ,Stochastic Processes ,0303 health sciences ,Models, Genetic ,Biophysical Letter ,HDAC11 ,Chromosome ,HDAC4 ,Position effect ,Eukaryotic chromosome fine structure ,Histone deacetylase ,Chromosomes, Fungal ,psychological phenomena and processes ,030217 neurology & neurosurgery - Abstract
Gene expression noise varies with genomic position and is a driving force in the evolution of chromosome organization. Nevertheless, position effects remain poorly characterized. Here, we present a systematic analysis of chromosomal position effects by characterizing single-cell gene expression from euchromatic positions spanning the length of a eukaryotic chromosome. We demonstrate that position affects gene expression by modulating the size of transcriptional bursts, rather than their frequency, and that the histone deacetylase Sir2 plays a role in this process across the chromosome.
- Published
- 2011
48. Clinical and genetic study of hereditary spastic paraplegia in Canada
- Author
-
Karim Mourabit-Amari, Pierre Provencher, Peter N. Ray, Jean-Denis Brisson, Anna Szuto, Patrick A. Dion, Noreen Mohsin, Nicolas Dupré, Shiyi Chen, Guy A. Rouleau, Anil Venkitachalam, Grace Yoon, Kym M. Boycott, Sohnee Ahmed, Dimitri J. Stavropoulos, Setareh Ashtiani, Oksana Suchowersky, Ziv Gan-Or, Heather MacDonald, Nicolas Chrestian, and Jodi Warman-Chardon
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Multivariate analysis ,Hereditary spastic paraplegia ,business.industry ,Odds ratio ,medicine.disease ,Article ,Confidence interval ,3. Good health ,03 medical and health sciences ,KIAA0196 ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,Cohort ,medicine ,Spastic ,Neurology (clinical) ,Paraplegia ,business ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
Objective:To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional outcomes for patients with HSP.Methods:We conducted a multicenter observational study of patients who met clinical criteria for the diagnosis of HSP in the provinces of Alberta, Ontario, and Quebec from 2012 to 2015. Characteristics of the participants were analyzed using descriptive statistics. The main outcome measure for a subset of the cohort (n = 48) was the Spastic Paraplegia Rating Scale. We also used the SPATAX-EUROSPA disability stage (disability score) to assess disability (n = 65).Results:A total of 526 patients were identified with HSP across the country, and 150 patients had a confirmed genetic diagnosis. Mutations were identified in 15 different genes; the most common were SPAST (SPG4, 48%), ATL1 (SPG3A, 16%), SPG11 (8%), SPG7 (7%), and KIAA0196 (SPG8, 5%). The diagnosis of SPG4 was associated with older age at symptom onset (p = 0.0017). SPG4 and SPG3A were less associated with learning disabilities compared to other subtypes of HSP, and SPG11 was strongly associated with progressive cognitive deficits (odds ratio 87.75, 95% confidence interval 14.04–548.24, p < 0.0001). SPG3A was associated with better functional outcomes compared to other HSP subtypes (p = 0.04) on multivariate analysis. The strongest predictor of significant disability was abnormal brain MRI (p = 0.014).Conclusions:The most important predictors of disability in our HSP cohort were SPG11 mutations and abnormal brain MRI. Accurate molecular characterization of well-phenotyped cohorts and international collaboration are essential to establish the natural history of these rare neurodegenerative disorders.
- Published
- 2016
49. Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia
- Author
-
Gan-Or, Ziv, primary, Bouslam, Naima, additional, Birouk, Nazha, additional, Lissouba, Alexandra, additional, Chambers, Daniel B., additional, Vérièpe, Julie, additional, Androschuk, Alaura, additional, Laurent, Sandra B., additional, Rochefort, Daniel, additional, Spiegelman, Dan, additional, Dionne-Laporte, Alexandre, additional, Szuto, Anna, additional, Liao, Meijiang, additional, Figlewicz, Denise A., additional, Bouhouche, Ahmed, additional, Benomar, Ali, additional, Yahyaoui, Mohamed, additional, Ouazzani, Reda, additional, Yoon, Grace, additional, Dupré, Nicolas, additional, Suchowersky, Oksana, additional, Bolduc, Francois V., additional, Parker, J. Alex, additional, Dion, Patrick A., additional, Drapeau, Pierre, additional, Rouleau, Guy A., additional, and Ouled Amar Bencheikh, Bouchra, additional
- Published
- 2016
- Full Text
- View/download PDF
50. Functional Outcomes in Hereditary Spastic Paraplegia: A Prospective Cohort Study (S43.005)
- Author
-
Chrestian, Nicolas, primary, Dupre, Nicolas, additional, Brisson, Jean-Denis, additional, Gan-Or, Ziv, additional, Szuto, Anna, additional, Chen, Shiyi, additional, Venkitachalam, Anil, additional, Warman Chardon, Jodi, additional, Ahmed, Sohnee, additional, Ashtiani, Setareh, additional, MacDonald, Heather, additional, Provencher, Pierre, additional, Boycott, Kym, additional, Stravropoulos, Dimitri, additional, Dion, Patrick, additional, Ray, Peter, additional, Suchowersky, Oksana, additional, Rouleau, Guy, additional, and Yoon, Grace, additional
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.