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1. RNA variant assessment using transactivation and transdifferentiation

Author

Azmanov, Dimitar N., Barnett, Christopher P., Barry, Simon C., Baynam, Gareth, Berkovic, Samuel F., Christodoulou, John, Coman, David J., Cooper, Sandra, Corbett, Mark A., Delatycki, Martin, Dudding, Tracy E., Fletcher, Sue, Gardner, Alison E., Gecz, Jozef, Higgins, Megan J., Hildebrand, Michael S., Jolly, Lachlan A., Lister, Ryan, McGaughran, Julie, Pflueger, Christian, Poulton, Cathryn, Roscioli, Tony, Hamish S. Scott, Ingrid Scheffer, Sinclair, Andrew H., Spurdle, Amanda B., Tan, Tiong Y., van Eyk, Clare L., Voineagu, Irina, Nicolas-Martinez, Emmylou C., Robinson, Olivia, Gardner, Alison, Ritchie, Tarin, Kroes, Thessa, Scheffer, Ingrid E., Barnier, Jean-Vianney, Rousseau, Véronique, Genevieve, David, Haushalter, Virginie, Piton, Amélie, Denommé-Pichon, Anne-Sophie, Bruel, Ange-Line, Nambot, Sophie, Isidor, Bertrand, Grigg, John, Gonzalez, Tina, Ghedia, Sondhya, Marchant, Rhett G., Bournazos, Adam, Wong, Wui-Kwan, Webster, Richard I., Evesson, Frances J., Jones, Kristi J., and Cooper, Sandra T.

Published
2024
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2. Cardiac and pulmonary findings in dysferlinopathy: A 3‐year, longitudinal study

Author

Moore, Ursula, Fernandez‐Torron, Roberto, Jacobs, Marni, Gordish‐Dressman, Heather, Diaz‐Manera, Jordi, James, Meredith K, Mayhew, Anna G, Harris, Elizabeth, Guglieri, Michela, Rufibach, Laura E, Feng, Jia, Blamire, Andrew M, Carlier, Pierre G, Spuler, Simone, Day, John W, Jones, Kristi J, Bharucha‐Goebel, Diana X, Salort‐Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C, Paradas, Carmen, Stojkovic, Tanya, Mori‐Yoshimura, Madoka, Bravver, Elena, Pegoraro, Elena, Lowes, Linda Pax, Mendell, Jerry R, Bushby, Kate, Consortium, The Jain COS, Bourke, John, and Straub, Volker

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Cardiovascular, Heart Disease, Lung, Clinical Research, Electrocardiography, Female, Humans, Longitudinal Studies, Male, Muscular Dystrophies, Limb-Girdle, Phenotype, Jain COS Consortium, Miyoshi myopathy, cardiac, dysferlin, limb girdle muscular dystrophy R2, respiratory, Medical and Health Sciences, Neurology & Neurosurgery, Biological sciences, Biomedical and clinical sciences
Abstract

Introduction/aimsThere is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype.MethodsAs part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo).ResultsMean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population.DiscussionThese results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.

Published
2022

4. Expanding the muscle imaging spectrum in dysferlinopathy: description of an outlier population from the classical MRI pattern

Author

Llansó, Laura, Moore, Ursula, Bolano-Diaz, Carla, James, Meredith, Blamire, Andrew M., Carlier, Pierre G., Rufibach, Laura, Gordish-Dressman, Heather, Boyle, Georgina, Hilsden, Heather, Day, John W., Jones, Kristi J., Bharucha-Goebel, Diana X., Salort-Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C., Paradas, Carmen, Stojkovic, Tanya, Mori-Yoshimura, Madoka, Bravver, Elena, Pegoraro, Elena, Mendell, Jerry R., Straub, Volker, and Díaz-Manera, Jordi

Published
2023
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5. Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency

Author

Gallon, Richard, Phelps, Rachel, Hayes, Christine, Brugieres, Laurence, Guerrini-Rousseau, Léa, Colas, Chrystelle, Muleris, Martine, Ryan, Neil A.J., Evans, D. Gareth, Grice, Hannah, Jessop, Emily, Kunzemann-Martinez, Annabel, Marshall, Lilla, Schamschula, Esther, Oberhuber, Klaus, Azizi, Amedeo A., Baris Feldman, Hagit, Beilken, Andreas, Brauer, Nina, Brozou, Triantafyllia, Dahan, Karin, Demirsoy, Ugur, Florkin, Benoît, Foulkes, William, Januszkiewicz-Lewandowska, Danuta, Jones, Kristi J., Kratz, Christian P., Lobitz, Stephan, Meade, Julia, Nathrath, Michaela, Pander, Hans-Jürgen, Perne, Claudia, Ragab, Iman, Ripperger, Tim, Rosenbaum, Thorsten, Rueda, Daniel, Sarosiek, Tomasz, Sehested, Astrid, Spier, Isabel, Suerink, Manon, Zimmermann, Stefanie-Yvonne, Zschocke, Johannes, Borthwick, Gillian M., Wimmer, Katharina, Burn, John, Jackson, Michael S., and Santibanez-Koref, Mauro

Published
2023
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6. Myostatin and follistatin as monitoring and prognostic biomarkers in dysferlinopathy

Author

Moore, Ursula, Fernández-Simón, Esther, Schiava, Marianela, Cox, Dan, Gordish-Dressman, Heather, James, Meredith K., Mayhew, Anna, Wilson, Ian, Guglieri, Michela, Rufibach, Laura, Blamire, Andrew, Carlier, Pierre G., Mori-Yoshimura, Madoka, Day, John W., Jones, Kristi J., Bharucha-Goebel, Diana X., Salort-Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C., Paradas, Carmen, Stojkovic, Tanya, Bravver, Elena, Pegoraro, Elena, Mendell, Jerry R., Bushby, Kate, Diaz-Manera, Jordi, and Straub, Volker

Published
2023
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7. Genomic multidisciplinary teams: A model for navigating genetic mainstreaming and precision medicine

Author

Ma, Alan, primary, Newing, Timothy P, additional, O'Shea, Rosie, additional, Gokoolparsadh, Akira, additional, Murdoch, Emma, additional, Hayward, Janette, additional, Shannon, Gillian, additional, Kevin, Lucy, additional, Bennetts, Bruce, additional, Ho, Gladys, additional, Smith, Janine, additional, Shah, Margit, additional, Jones, Kristi J, additional, Josephi‐Taylor, Sarah, additional, Sandaradura, Sarah A, additional, Adès, Lesley, additional, Jamieson, Robyn, additional, and Rankin, Nicole M, additional

Published
2024
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8. Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

Author

Marchant, Rhett G., primary, Bryen, Samantha J., additional, Bahlo, Melanie, additional, Cairns, Anita, additional, Chao, Katherine R., additional, Corbett, Alastair, additional, Davis, Mark R., additional, Ganesh, Vijay S., additional, Ghaoui, Roula, additional, Jones, Kristi J., additional, Kornberg, Andrew J., additional, Lek, Monkol, additional, Liang, Christina, additional, MacArthur, Daniel G., additional, Oates, Emily C., additional, O'Donnell‐Luria, Anne, additional, O'Grady, Gina L., additional, Osei‐Owusu, Ikeoluwa A., additional, Rafehi, Haloom, additional, Reddel, Stephen W., additional, Roxburgh, Richard H., additional, Ryan, Monique M., additional, Sandaradura, Sarah A., additional, Scott, Liam W., additional, Valkanas, Elise, additional, Weisburd, Ben, additional, Young, Helen, additional, Evesson, Frances J., additional, Waddell, Leigh B., additional, and Cooper, Sandra T., additional

Published
2024
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10. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Author

Koczkowska, Magdalena, Callens, Tom, Gomes, Alicia, Sharp, Angela, Chen, Yunjia, Hicks, Alesha D, Aylsworth, Arthur S, Azizi, Amedeo A, Basel, Donald G, Bellus, Gary, Bird, Lynne M, Blazo, Maria A, Burke, Leah W, Cannon, Ashley, Collins, Felicity, DeFilippo, Colette, Denayer, Ellen, Digilio, Maria C, Dills, Shelley K, Dosa, Laura, Greenwood, Robert S, Griffis, Cristin, Gupta, Punita, Hachen, Rachel K, Hernández-Chico, Concepción, Janssens, Sandra, Jones, Kristi J, Jordan, Justin T, Kannu, Peter, Korf, Bruce R, Lewis, Andrea M, Listernick, Robert H, Lonardo, Fortunato, Mahoney, Maurice J, Ojeda, Mayra Martinez, McDonald, Marie T, McDougall, Carey, Mendelsohn, Nancy, Miller, David T, Mori, Mari, Oostenbrink, Rianne, Perreault, Sebastién, Pierpont, Mary Ella, Piscopo, Carmelo, Pond, Dinel A, Randolph, Linda M, Rauen, Katherine A, Rednam, Surya, Rutledge, S Lane, Saletti, Veronica, Schaefer, G Bradley, Schorry, Elizabeth K, Scott, Daryl A, Shugar, Andrea, Siqveland, Elizabeth, Starr, Lois J, Syed, Ashraf, Trapane, Pamela L, Ullrich, Nicole J, Wakefield, Emily G, Walsh, Laurence E, Wangler, Michael F, Zackai, Elaine, Claes, Kathleen BM, Wimmer, Katharina, van Minkelen, Rick, De Luca, Alessandro, Martin, Yolanda, Legius, Eric, and Messiaen, Ludwine M

Subjects
Biological Sciences, Genetics, Pediatric, Rare Diseases, Neurofibromatosis, Clinical Research, Neurosciences, Brain Disorders, Adolescent, Adult, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Learning Disabilities, Male, Mutation, Missense, Neurofibroma, Plexiform, Neurofibromatosis 1, Neurofibromin 1, Sequence Deletion, Young Adult, NF1, p.Met992del, genotype-phenotype correlation, neurofibroma, learning difficulties, genotype–phenotype correlation, Clinical Sciences, Genetics & Heredity
Abstract

PurposeNeurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.MethodsA total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.ResultsNone of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.ConclusionWe demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Published
2019

11. Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies

Author

Dworschak, Gabriel C., Punetha, Jaya, Kalanithy, Jeshurun C., Mingardo, Enrico, Erdem, Haktan B., Akdemir, Zeynep C., Karaca, Ender, Mitani, Tadahiro, Marafi, Dana, Fatih, Jawid M., Jhangiani, Shalini N., Hunter, Jill V., Dakal, Tikam Chand, Dhabhai, Bhanupriya, Dabbagh, Omar, Alsaif, Hessa S., Alkuraya, Fowzan S., Maroofian, Reza, Houlden, Henry, Efthymiou, Stephanie, Dominik, Natalia, Salpietro, Vincenzo, Sultan, Tipu, Haider, Shahzad, Bibi, Farah, Thiele, Holger, Hoefele, Julia, Riedhammer, Korbinian M., Wagner, Matias, Guella, Ilaria, Demos, Michelle, Keren, Boris, Buratti, Julien, Charles, Perrine, Nava, Caroline, Héron, Delphine, Heide, Solveig, Valkanas, Elise, Waddell, Leigh B., Jones, Kristi J., Oates, Emily C., Cooper, Sandra T., MacArthur, Daniel, Syrbe, Steffen, Ziegler, Andreas, Platzer, Konrad, Okur, Volkan, Chung, Wendy K., O’Shea, Sarah A., Alcalay, Roy, Fahn, Stanley, Mark, Paul R., Guerrini, Renzo, Vetro, Annalisa, Hudson, Beth, Schnur, Rhonda E., Hoganson, George E., Burton, Jennifer E., McEntagart, Meriel, Lindenberg, Tobias, Yilmaz, Öznur, Odermatt, Benjamin, Pehlivan, Davut, Posey, Jennifer E., Lupski, James R., and Reutter, Heiko

Published
2021
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12. Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease

Author

Moore, Ursula, Gordish, Heather, Diaz-Manera, Jordi, James, Meredith K., Mayhew, Anna G., Guglieri, Michela, Fernandez-Torron, Roberto, Rufibach, Laura E., Feng, Jia, Blamire, Andrew M., Carlier, Pierre G., Spuler, Simone, Day, John W., Jones, Kristi J., Bharucha-Goebel, Diana X., Salort-Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C., Paradas, Carmen, Stojkovic, Tanya, Mori-Yoshimura, Madoka, Bravver, Elena, Pegoraro, Elena, Lowes, Linda Pax, Mendell, Jerry R., Bushby, Kate, and Straub, Volker

Published
2021
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15. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

Alfano, Lindsay N, Eagle, Michelle, James, Meredith K, Lowes, Linda, Mayhew, Anna, Mazzone, Elena S, Nelson, Leslie, Rose, Kristy J, Abdel-Hamid, Hoda Z, Apkon, Susan D, Barohn, Richard J, Bertini, Enrico, Bloetzer, Clemens, de Vaud, Lausanne Canton, Butterfield, Russell J, Chabrol, Brigitte, Chae, Jong-Hee, Jongno-gu, Daehak-ro, Comi, Giacomi Pietro, Darras, Basil T, Dastgir, Jahannaz, Desguerre, Isabelle, Escobar, Raul G, Finanger, Erika, Guglieri, Michela, Hughes, Imelda, Iannaccone, Susan T, Jones, Kristi J, Karachunski, Peter, Kudr, Martin, Lotze, Timothy, Mah, Jean K, Mathews, Katherine, Nevo, Yoram, Parsons, Julie, Péréon, Yann, de Queiroz Campos Araujo, Alexandra Prufer, Renfroe, J Ben, de Resende, Maria Bernadete Dutra, Ryan, Monique, Selby, Kathryn, Tennekoon, Gihan, Vita, Giuseppe, McDonald, Craig M, Campbell, Craig, Torricelli, Ricardo Erazo, Finkel, Richard S, Flanigan, Kevin M, Goemans, Nathalie, Heydemann, Peter, Kaminska, Anna, Kirschner, Janbernd, Muntoni, Francesco, Osorio, Andrés Nascimento, Schara, Ulrike, Sejersen, Thomas, Shieh, Perry B, Sweeney, H Lee, Topaloglu, Haluk, Tulinius, Már, Vilchez, Juan J, Voit, Thomas, Wong, Brenda, Elfring, Gary, Kroger, Hans, Luo, Xiaohui, McIntosh, Joseph, Ong, Tuyen, Riebling, Peter, Souza, Marcio, Spiegel, Robert J, Peltz, Stuart W, and Mercuri, Eugenio

Published
2017
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16. The relationship between beta-ureidopropionase deficiency due to UPB1 variants and human phenotypes is uncertain

Author

Righetti, Sarah, Allcock, Richard J. N., Yaplito-Lee, Joy, Adams, Louisa, Ellaway, Carolyn, Jones, Kristi J., Selvanathan, Arthavan, Fletcher, Janice, Pitt, James, van Kuilenburg, André B. P., Delatycki, Martin B., Laing, Nigel G., Kirk, Edwin P., Laboratory Genetic Metabolic Diseases, and Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Literature review, Purine-Pyrimidine Metabolism, Inborn Errors, Brain Diseases, Movement Disorders, Carrier frequency, Endocrinology, Diabetes and Metabolism, UPB1, Beta-ureidopropionase deficiency, Biochemistry, Phenotype, Endocrinology, β-ureidopropionase, Genetics, Humans, Variant, Molecular Biology
Abstract

Background: Beta-ureidopropionase deficiency, caused by variants in UPB1, has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism. Aim: We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype. Methods: Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases. Results: Fifty-three published cases were identified, and two additional cases are reported here. Of these, 14 were asymptomatic and four had transient neurological features; clinical features in the remainder were variable and included non-neurological presentations. Several of the variants previously reported as pathogenic are present in population databases at frequencies higher than expected for a rare condition. In particular, the variant most frequently reported as pathogenic, p.Arg326Gln, is very common among East Asians, with a carrier frequency of 1 in 19 and 1 in 907 being homozygous for the variant in gnomAD v2.1.1. Conclusion: Pending the availability of further evidence, UPB1 should be considered a ‘gene of uncertain clinical significance’. Caution should be used in ascribing clinical significance to biochemical features of beta-ureidopropionase deficiency and/or UPB1 variants in patients with neurodevelopmental phenotypes. UPB1 is not currently suitable for inclusion in gene panels for reproductive genetic carrier screening. Synopsis: The relationship between beta-ureidopropionase deficiency due to UPB1 variants and clinical phenotypes is uncertain.

Published
2022

17. Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

Author

Lunke, Sebastian, Eggers, Stefanie, Wilson, Meredith, Patel, Chirag, Barnett, Christopher P., Pinner, Jason, Sandaradura, Sarah A., Buckley, Michael F., Krzesinski, Emma I., de Silva, Michelle G., Brett, Gemma R., Boggs, Kirsten, Mowat, David, Kirk, Edwin P., Adès, Lesley C., Akesson, Lauren S., Amor, David J., Ayres, Samantha, Baxendale, Anne, Borrie, Sarah, Bray, Alessandra, Brown, Natasha J., Chan, Cheng Yee, Chong, Belinda, Cliffe, Corrina, Delatycki, Martin B., Edwards, Matthew, Elakis, George, Fahey, Michael C., Fennell, Andrew, Fowles, Lindsay, Gallacher, Lyndon, Higgins, Megan, Howell, Katherine B., Hunt, Lauren, Hunter, Matthew F., Jones, Kristi J., King, Sarah, Kumble, Smitha, Lang, Sarah, Le Moing, Maelle, Ma, Alan, Phelan, Dean, Quinn, Michael C. J., Richards, Anna, Richmond, Christopher M., Riseley, Jessica, Rodgers, Jonathan, Sachdev, Rani, Sadedin, Simon, Schlapbach, Luregn J., Smith, Janine, Springer, Amanda, Tan, Natalie B., Tan, Tiong Y., Temple, Suzanna L., Theda, Christiane, Vasudevan, Anand, White, Susan M., Yeung, Alison, Zhu, Ying, Martyn, Melissa, Best, Stephanie, Roscioli, Tony, Christodoulou, John, and Stark, Zornitza

Published
2020
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18. Assessment of disease progression in dysferlinopathy: A 1-year cohort study

Author

Moore, Ursula, Jacobs, Marni, James, Meredith K., Mayhew, Anna G., Fernandez-Torron, Roberto, Feng, Jia, Cnaan, Avital, Eagle, Michelle, Bettinson, Karen, Rufibach, Laura E., Lofra, Robert Muni, Blamire, Andrew M., Carlier, Pierre G., Mittal, Plavi, Lowes, Linda Pax, Alfano, Lindsay, Rose, Kristy, Duong, Tina, Berry, Katherine M., Montiel-Morillo, Elena, Pedrosa-Hernández, Irene, Holsten, Scott, Sanjak, Mohammed, Ashida, Ai, Sakamoto, Chikako, Tateishi, Takayuki, Yajima, Hiroyuki, Canal, Aurélie, Ollivier, Gwenn, Decostre, Valerie, Mendez, Juan Bosco, Sánchez-Aguilera Praxedes, Nieves, Thiele, Simone, Siener, Catherine, Shierbecker, Jeanine, Florence, Julaine M., Vandevelde, Bruno, DeWolf, Brittney, Hutchence, Meghan, Gee, Richard, Prügel, Juliana, Maron, Elke, Hilsden, Heather, Lochmüller, Hanns, Grieben, Ulrike, Spuler, Simone, Tesi Rocha, Carolina, Day, John W., Jones, Kristi J., Bharucha-Goebel, Diana X., Salort-Campana, Emmanuelle, Harms, Matthew, Pestronk, Alan, Krause, Sabine, Schreiber-Katz, Olivia, Walter, Maggie C., Paradas, Carmen, Hogrel, Jean-Yves, Stojkovic, Tanya, Takeda, Shinʼichi, Mori-Yoshimura, Madoka, Bravver, Elena, Sparks, Susan, Díaz-Manera, Jordi, Bello, Luca, Semplicini, Claudio, Pegoraro, Elena, Mendell, Jerry R., Bushby, Kate, and Straub, Volker

Published
2019
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19. Prevalence, parameters, and pathogenic mechanisms for splice-altering acceptor variants that disrupt the AG exclusion zone

Author

Bryen, Samantha J., primary, Yuen, Michaela, additional, Joshi, Himanshu, additional, Dawes, Ruebena, additional, Zhang, Katharine, additional, Lu, Jessica K., additional, Jones, Kristi J., additional, Liang, Christina, additional, Wong, Wui-Kwan, additional, Peduto, Anthony J., additional, Waddell, Leigh B., additional, Evesson, Frances J., additional, and Cooper, Sandra T., additional

Published
2022
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20. Water T2 could predict functional decline in patients with dysferlinopathy

Author

Moore, Ursula, Caldas de Almeida Araújo, Ericky, Reyngoudt, Harmen, Gordish-Dressman, Heather, Smith, Fiona E, Wilson, Ian, James, Meredith, Mayhew, Anna, Rufibach, Laura, Day, John W, Jones, Kristi J, Bharucha-Goebel, Diana X, Salort-Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C, Paradas, Carmen, Stojkovic, Tanya, Mori-Yoshimura, Madoka, Bravver, Elena, Pegoraro, Elena, Mendell, Jerry R, Jain COS Consortium, Bushby, Kate, Blamire, Andrew M, Straub, Volker, Carlier, Pierre G, Diaz-Manera, Jordi, Jain Foundation, and Diaz-Manera, Jordi

Subjects
Limb girdle muscular dystrophy, Magnetic resonance imaging, Muscular Dystrophies, Limb-Girdle, Physiology (medical), Limb girdle muscular dystrophy 2B, Limb girdle muscular dystrophy R2, Humans, Water, Orthopedics and Sports Medicine, Water T2, Muscle, Skeletal, Muscular Dystrophies
Abstract

[Background]: Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies., [Methods]: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function., [Results]: A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (, [Conclusions]: In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials., The Jain COS consortium would like to thank the study participants and their families for their invaluable contribution and would also like to acknowledge the ongoing support the Jain Foundation provides in the development, management, and analysis of this study. The Jain Foundation, based in Seattle, USA, is entirely focused on LGMD2B/dysferlinopathy/Miyoshi myopathy. The foundation does not solicit funding from patients but instead funds research and clinical studies worldwide with the goal of finding treatments for dysferlinopathy.

Published
2022

21. Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant

Author

Sandaradura, Sarah A., Bournazos, Adam, Mallawaarachchi, Amali, Cummings, Beryl B., Waddell, Leigh B., Jones, Kristi J., Troedson, Christopher, Sudarsanam, Annapurna, Nash, Benjamin M., Peters, Gregory B., Algar, Elizabeth M., MacArthur, Daniel G., North, Kathryn N., Brammah, Susan, Charlton, Amanda, Laing, Nigel G., Wilson, Meredith J., Davis, Mark R., and Cooper, Sandra T.

Published
2018
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22. Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Author

Koczkowska, Magdalena, Callens, Tom, Gomes, Alicia, Sharp, Angela, Chen, Yunjia, Hicks, Alesha D., Aylsworth, Arthur S., Azizi, Amedeo A., Basel, Donald G., Bellus, Gary, Bird, Lynne M., Blazo, Maria A., Burke, Leah W., Cannon, Ashley, Collins, Felicity, DeFilippo, Colette, Denayer, Ellen, Digilio, Maria C., Dills, Shelley K., Dosa, Laura, Greenwood, Robert S., Griffis, Cristin, Gupta, Punita, Hachen, Rachel K., Hernández-Chico, Concepción, Janssens, Sandra, Jones, Kristi J., Jordan, Justin T., Kannu, Peter, Korf, Bruce R., Lewis, Andrea M., Listernick, Robert H., Lonardo, Fortunato, Mahoney, Maurice J., Ojeda, Mayra Martinez, McDonald, Marie T., McDougall, Carey, Mendelsohn, Nancy, Miller, David T., Mori, Mari, Oostenbrink, Rianne, Perreault, Sebastién, Pierpont, Mary Ella, Piscopo, Carmelo, Pond, Dinel A., Randolph, Linda M., Rauen, Katherine A., Rednam, Surya, Rutledge, S. Lane, Saletti, Veronica, Schaefer, G. Bradley, Schorry, Elizabeth K., Scott, Daryl A., Shugar, Andrea, Siqveland, Elizabeth, Starr, Lois J., Syed, Ashraf, Trapane, Pamela L., Ullrich, Nicole J., Wakefield, Emily G., Walsh, Laurence E., Wangler, Michael F., Zackai, Elaine, Claes, Kathleen B. M., Wimmer, Katharina, van Minkelen, Rick, De Luca, Alessandro, Martin, Yolanda, Legius, Eric, and Messiaen, Ludwine M.

Published
2019
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23. Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach

Author

Mayhew, Anna G., primary, James, Meredith K., additional, Moore, Ursula, additional, Sutherland, Helen, additional, Jacobs, Marni, additional, Feng, Jia, additional, Lowes, Linda Pax, additional, Alfano, Lindsay N., additional, Muni Lofra, Robert, additional, Rufibach, Laura E., additional, Rose, Kristy, additional, Duong, Tina, additional, Bello, Luca, additional, Pedrosa-Hernández, Irene, additional, Holsten, Scott, additional, Sakamoto, Chikako, additional, Canal, Aurélie, additional, Sánchez-Aguilera Práxedes, Nieves, additional, Thiele, Simone, additional, Siener, Catherine, additional, Vandevelde, Bruno, additional, DeWolf, Brittney, additional, Maron, Elke, additional, Gordish-Dressman, Heather, additional, Hilsden, Heather, additional, Guglieri, Michela, additional, Hogrel, Jean-Yves, additional, Blamire, Andrew M., additional, Carlier, Pierre G., additional, Spuler, Simone, additional, Day, John W., additional, Jones, Kristi J., additional, Bharucha-Goebel, Diana X., additional, Salort-Campana, Emmanuelle, additional, Pestronk, Alan, additional, Walter, Maggie C., additional, Paradas, Carmen, additional, Stojkovic, Tanya, additional, Mori-Yoshimura, Madoka, additional, Bravver, Elena, additional, Díaz-Manera, Jordi, additional, Pegoraro, Elena, additional, Mendell, Jerry R., additional, and Straub, Volker, additional

Published
2022
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24. Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants

Author

Bournazos, Adam M., primary, Riley, Lisa G., additional, Bommireddipalli, Shobhana, additional, Ades, Lesley, additional, Akesson, Lauren S., additional, Al-Shinnag, Mohammad, additional, Alexander, Stephen I., additional, Archibald, Alison D., additional, Balasubramaniam, Shanti, additional, Berman, Yemima, additional, Beshay, Victoria, additional, Boggs, Kirsten, additional, Bojadzieva, Jasmina, additional, Brown, Natasha J., additional, Bryen, Samantha J., additional, Buckley, Michael F., additional, Chong, Belinda, additional, Davis, Mark R., additional, Dawes, Ruebena, additional, Delatycki, Martin, additional, Donaldson, Liz, additional, Downie, Lilian, additional, Edwards, Caitlin, additional, Edwards, Matthew, additional, Engel, Amanda, additional, Ewans, Lisa J., additional, Faiz, Fathimath, additional, Fennell, Andrew, additional, Field, Michael, additional, Freckmann, Mary-Louise, additional, Gallacher, Lyndon, additional, Gear, Russell, additional, Goel, Himanshu, additional, Goh, Shuxiang, additional, Goodwin, Linda, additional, Hanna, Bernadette, additional, Harraway, James, additional, Higgins, Megan, additional, Ho, Gladys, additional, Hopper, Bruce K., additional, Horton, Ari E., additional, Hunter, Matthew F., additional, Huq, Aamira J., additional, Josephi-Taylor, Sarah, additional, Joshi, Himanshu, additional, Kirk, Edwin, additional, Krzesinski, Emma, additional, Kumar, Kishore R., additional, Lemckert, Frances, additional, Leventer, Richard J., additional, Lindsey-Temple, Suzanna E., additional, Lunke, Sebastian, additional, Ma, Alan, additional, Macaskill, Steven, additional, Mallawaarachchi, Amali, additional, Marty, Melanie, additional, Marum, Justine E., additional, McCarthy, Hugh J., additional, Menezes, Manoj P., additional, McLean, Alison, additional, Milnes, Di, additional, Mohammad, Shekeeb, additional, Mowat, David, additional, Niaz, Aram, additional, Palmer, Elizabeth E., additional, Patel, Chirag, additional, Patel, Shilpan G., additional, Phelan, Dean, additional, Pinner, Jason R., additional, Rajagopalan, Sulekha, additional, Regan, Matthew, additional, Rodgers, Jonathan, additional, Rodrigues, Miriam, additional, Roxburgh, Richard H., additional, Sachdev, Rani, additional, Roscioli, Tony, additional, Samarasekera, Ruvishani, additional, Sandaradura, Sarah A., additional, Savva, Elena, additional, Schindler, Tim, additional, Shah, Margit, additional, Sinnerbrink, Ingrid B., additional, Smith, Janine M., additional, Smith, Richard J., additional, Springer, Amanda, additional, Stark, Zornitza, additional, Strom, Samuel P., additional, Sue, Carolyn M., additional, Tan, Kenneth, additional, Tan, Tiong Y., additional, Tantsis, Esther, additional, Tchan, Michel C., additional, Thompson, Bryony A., additional, Trainer, Alison H., additional, van Spaendonck-Zwarts, Karin, additional, Walsh, Rebecca, additional, Warwick, Linda, additional, White, Stephanie, additional, White, Susan M., additional, Williams, Mark G., additional, Wilson, Meredith J., additional, Wong, Wui Kwan, additional, Wright, Dale C., additional, Yap, Patrick, additional, Yeung, Alison, additional, Young, Helen, additional, Jones, Kristi J., additional, Bennetts, Bruce, additional, Cooper, Sandra T., additional, Abdulrasool, Ghusoon, additional, Al Eryani, Ghamdan, additional, Arts, Peer, additional, Bagnall, Richard, additional, Baker, Naomi L., additional, Barnett, Christopher, additional, Beecroft, Sarah, additional, Berbic, Marina, additional, Black, Michael, additional, Blackburn, Jim, additional, Blombery, Piers, additional, Bournazos, Adam M., additional, Branford, Susan, additional, Breen, Jimmy, additional, Burnett, Leslie, additional, Canson, Daffodil, additional, Cheong, Pak, additional, Chew, Edward, additional, Christodoulou, John, additional, Chung, Seo-Kyung, additional, Clark, Mike, additional, Cliffe, Corrina, additional, Cole, Melissa, additional, Collins, Felicity, additional, Compton, Alison, additional, Cooper, Antony, additional, Corbett, Mark, additional, Cowley, Mark, additional, Dudding, Tracy, additional, Eggers, Stefanie, additional, Eyras, Eduardo, additional, Fernandez, Miriam Fanjul, additional, Fellowes, Andrew, additional, Fleischer, Ron, additional, Folland, Chiara, additional, Fox, Lucy, additional, Gaff, Clara, additional, Galea, Melanie, additional, Ghaoui, Roula, additional, Gornanitis, Ilias, additional, Ha, Thuong, additional, Hayashi, Rippei, additional, Hayes, Ian, additional, Henderson, Alex, additional, Hesson, Luke, additional, Heyer, Erin, additional, Hildebrand, Michael, additional, Hipwell, Michael, additional, Hoskins, Cass, additional, Jackson, Matilda, additional, James, Paul, additional, Wong, Justin Jong-Leong, additional, Kassahn, Karin, additional, Kaub, Peter, additional, Kevin, Lucy, additional, Kumble, Smitha, additional, Kummerfeld, Sarah, additional, Laing, Nigel, additional, Lau, Chiyan, additional, Lee, Eric, additional, Leighton, Sarah, additional, Lundie, Ben, additional, Mayoh, Chelsea, additional, McGaughran, Julie, additional, McPhillips, Mary, additional, Meldrum, Cliff, additional, Middleton, Edwina, additional, Mina, Kym, additional, Nisselle, Amy, additional, Oates, Emily, additional, Oshlack, Alicia, additional, Parasivam, Gayathri, additional, Parsons, Michael, additional, Quinn, Michael, additional, Rasko, John, additional, Ravenscroft, Gina, additional, Ravine, Anja, additional, Recsei, Krista, additional, Rehn, Jacqueline, additional, Robertson, Stephen, additional, Ronan, Anne, additional, Ryland, Georgina, additional, Sadedin, Simon, additional, Schreiber, Andreas, additional, Scott, Hamish, additional, Scott, Rodney, additional, Semsarian, Christopher, additional, Simons, Cas, additional, Singer, Emma, additional, Smyth, Renee, additional, Spurdle, Amanda, additional, Sullivan, Patricia, additional, Sundercombe, Samantha, additional, Thorburn, David, additional, Toubia, John, additional, Trent, Ronald, additional, Tudini, Emma, additional, Voneague, Irina, additional, Waddell, Leigh, additional, Walker, Logan, additional, Wallis, Mathew, additional, Warnock, Nick, additional, Weatheritt, Robert, additional, White, Deborah, additional, Winship, Ingrid, additional, Worgan, Lisa, additional, Wu, Kathy, additional, and Ziolowski, Andrew, additional

Published
2022
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25. Meta-analyses of deflazacort versus prednisone/prednisolone in patients with nonsense mutation Duchenne muscular dystrophy

Author

Shieh, Perry B, primary, Elfring, Gary, additional, Trifillis, Panayiota, additional, Santos, Claudio, additional, Peltz, Stuart W, additional, Parsons, Julie A, additional, Apkon, Susan, additional, Darras, Basil T, additional, Campbell, Craig, additional, McDonald, Craig M, additional, Barohn, Richard J, additional, Bertini, Enrico, additional, Bushby, Kate, additional, Chabrol, Brigitte, additional, Ciafaloni, Emma, additional, Columer, Jaume, additional, Comi, Giacomi Pietro, additional, Connolly, Anne, additional, Finkel, Richard S, additional, Flanigan, Kevin M, additional, Goemans, Nathalie, additional, Guglieri, Michela, additional, Iannaccone, Susan T, additional, Jones, Kristi J, additional, Kaufmann, Petra, additional, Kirschner, Janbernd, additional, Mah, Jean K, additional, Mathews, Katherine, additional, Mercuri, Eugenio, additional, Muntoni, Francesco, additional, Nevo, Yoram, additional, Osorio, Andrés Nascimento, additional, Péréon, Yann, additional, Quinlivan, Rosaline, additional, Renfroe, J. Ben, additional, Russman, Barry, additional, Ryan, Monique, additional, Sampson, Jacinda, additional, Schara, Ulrike, additional, Selby, Kathryn, additional, Sejersen, Thomas, additional, Sproule, Douglas M, additional, Sweeney, H. Lee, additional, Tulinius, Már, additional, Vilchez, Juan J, additional, Vita, Giuseppe, additional, Voit, Thomas, additional, Burns-Wechsler, Stephanie, additional, Wong, Brenda, additional, Abresch, Ted, additional, Henricson, Erik K, additional, Coleman, Kim, additional, Eagle, Michelle, additional, Florence, Julaine, additional, Gappmaier, Ed, additional, McDonald, Craig, additional, Abdel-Hamid, Hoda Z, additional, Bloetzer, Clemens, additional, Butterfield, Russell J, additional, Chae, Jong-Hee, additional, Dastgir, Jahannaz, additional, Desguerre, Isabelle, additional, Escobar, Raul G, additional, Finanger, Erika, additional, Heydemann, Peter, additional, Hughes, Imelda, additional, Kaminska, Anna, additional, Karachunski, Peter, additional, Kudr, Martin, additional, Lotze, Timothy, additional, de Queiroz Campos Araujo, Alexandra Prufer, additional, Dutra de Resende, Maria Bernadete, additional, Tennekoon, Gihan, additional, Topaloglu, Haluk, additional, Torricelli, Ricardo Erazo, additional, Alfano, Lindsay N, additional, James, Meredith K, additional, Lowes, Linda, additional, Mayhew, Anna, additional, Mazzone, Elena S, additional, Nelson, Leslie, additional, and Rose, Kristy J, additional

Published
2021
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26. L‐carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial

Author

Vasiljevski, Emily R., primary, Burns, Joshua, additional, Bray, Paula, additional, Donlevy, Gabrielle, additional, Mudge, Anita J., additional, Jones, Kristi J., additional, Summers, Matthew A., additional, Biggin, Andrew, additional, Munns, Craig F., additional, McKay, Marnee J., additional, Baldwin, Jennifer N., additional, Little, David G., additional, and Schindeler, Aaron, additional

Published
2021
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27. Assessing Dysferlinopathy Patients Over Three Years With a New Motor Scale

Author

Jacobs, Marni B, James, Meredoith K, Lowes, Linda P, Alfano, Lindsay N, Eagle, Michelle, Muni Lofra, Robert, Moore, Ursula, Feng, Jia, Rufibach, Laura E, Rose, Kristy, Duong, Tina, Bello, Luca, Pedrosa-Hernández, Irene, Holsten, Scott, Sakamoto, Chikako, Canal, Aurélie, Sanchez-Aguilera Práxedes, Nieves, Thiele, Simone, Siener, Catherine, Vandevelde, Bruno, DeWolf, Brittney, Maron, Elke, Guglieri, Michela, Hogrel, Jean-Yves, Blamire, Andrew M, Carlier, Pierre G, Spuler, Simone, Day, John W, Jones, Kristi J, Bharucha-Goebel, Diana X, Salort-Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C, Paradas, Carmen, Stojkovic, Tanya, Mori-Yoshimura, Madoka, Bravver, Elena, Díaz-Manera, Jordi, Pegoraro, Elena, Mendell, Jerry R, Jain COS Consortium, Mayhew, Anna G, Straub, Volker, Jain Foundation, and John Walton Centre Muscular Dystrophy Research Centre

Subjects
0301 basic medicine, Adult, Male, Dysferlinopathy, medicine.medical_specialty, Adolescent, Psychometrics, Disease, Age of Onset, Aged, Aged, 80 and over, Child, Clinical Trials as Topic, Cohort Studies, Disease Progression, Female, Humans, Longitudinal Studies, Middle Aged, Muscular Dystrophies, Limb-Girdle, Treatment Outcome, Young Adult, Muscular Dystrophies, 03 medical and health sciences, Limb-Girdle, 0302 clinical medicine, Physical medicine and rehabilitation, 80 and over, Medicine, Muscular dystrophy, Generalized estimating equation, Rasch model, business.industry, Clinical study design, medicine.disease, Clinical trial, 030104 developmental biology, Neurology, Cohort, Neurology (clinical), Function and Dysfunction of the Nervous System, business, 030217 neurology & neurosurgery
Abstract

The Jain COS Consortium., [Objective] Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD., [Methods] We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories., [Results] The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline., [Interpretation] The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967–978, The estimated US $4 million needed to fund this study was provided by the Jain Foundation. (www.jain-foundation.org) The Jain COS consortium would like to thank the study participants and their families for their invaluable contribution. The John Walton Centre Muscular Dystrophy Research Centre is part of the MRC Centre for Neuromuscular Diseases (Grant number MR/K000608/1).

Published
2021

28. Ataluren treatment of patients with nonsense mutation dystrophinopathy

Author

Bushby, Katharine, Finkel, Richard, Wong, Brenda, Barohn, Richard, Campbell, Craig, Comi, Giacomo P., Connolly, Anne M., Day, John W., Flanigan, Kevin M., Goemans, Nathalie, Jones, Kristi J., Mercuri, Eugenio, Quinlivan, Ros, Renfroe, James B., Russman, Barry, Ryan, Monique M., Tulinius, Mar, Voit, Thomas, Moore, Steven A., Lee Sweeney, H., Abresch, Richard T., Coleman, Kim L., Eagle, Michelle, Florence, Julaine, Gappmaier, Eduard, Glanzman, Allan M., Henricson, Erik, Barth, Jay, Elfring, Gary L., Reha, Allen, Spiegel, Robert J., Oʼdonnell, Michael W., Peltz, Stuart W., and Mcdonald, Craig M.

Published
2014
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29. WGS and RNA Studies Diagnose Noncoding DMD Variants in Males With High Creatine Kinase

Author

Waddell, Leigh B., primary, Bryen, Samantha J., additional, Cummings, Beryl B., additional, Bournazos, Adam, additional, Evesson, Frances J., additional, Joshi, Himanshu, additional, Marshall, Jamie L., additional, Tukiainen, Taru, additional, Valkanas, Elise, additional, Weisburd, Ben, additional, Sadedin, Simon, additional, Davis, Mark R., additional, Faiz, Fathimath, additional, Gooding, Rebecca, additional, Sandaradura, Sarah A., additional, O'Grady, Gina L., additional, Tchan, Michel C., additional, Mowat, David R., additional, Oates, Emily C., additional, Farrar, Michelle A., additional, Sampaio, Hugo, additional, Ma, Alan, additional, Neas, Katherine, additional, Wang, Min-Xia, additional, Charlton, Amanda, additional, Chan, Charles, additional, Kenwright, Diane N., additional, Graf, Nicole, additional, Arbuckle, Susan, additional, Clarke, Nigel F., additional, MacArthur, Daniel G., additional, Jones, Kristi J., additional, Lek, Monkol, additional, and Cooper, Sandra T., additional

Published
2021
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30. Integrating a Pilot Newborn Screening for Spinal Muscular Atrophy Into the Australian Public Healthcare System

Author

D'Silva, Arlene M., primary, Sampaio, Hugo, additional, Kariyawasam, Didu Sanduni Thamarasa, additional, Mowat, David, additional, Russell, Jacqui, additional, Junek, Zena, additional, Jones, Kristi J., additional, Alexander, Ian E., additional, Best, Stephanie, additional, Wiley, Veronica, additional, and Farrar, Michelle A., additional

Published
2021
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31. Mutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathy

Author

Compton, Alison G., Albrecht, Douglas E., Seto, Jane T., Cooper, Sandra T., Ilkovski, Biljana, Jones, Kristi J., Challis, Daniel, Mowat, David, Ranscht, Barbara, Bahlo, Melanie, Froehner, Stanley C., and North, Kathryn N.

Subjects
Lethal mutation -- Analysis, Muscle diseases -- Causes of, Muscle diseases -- Genetic aspects, Neuromuscular junction -- Research, Biological sciences
Abstract

Several studies are conducted to determine the causes and effects of a lethal congenital myopathy that is inherited in an autosomal-recessive manner and is characterized by the loss of [beta]2-syntrophin. The disorder is shown to be a result of the mutations caused in contactin-1, a neural adhesion and neuromuscular junction protein.

Published
2008

32. Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity on T1W Magnetic Resonance Imaging in Adults With Dysferlinopathy

Author

Moore, Ursula, primary, Jacobs, Marni, additional, Fernandez-Torron, Roberto, additional, LLauger Rossello, Jaume, additional, Smith, Fiona E., additional, James, Meredith, additional, Mayhew, Anna, additional, Rufibach, Laura, additional, Carlier, Pierre G., additional, Blamire, Andrew M., additional, Day, John W., additional, Jones, Kristi J., additional, Bharucha-Goebel, Diana X., additional, Salort-Campana, Emmanuelle, additional, Pestronk, Alan, additional, Walter, Maggie C., additional, Paradas, Carmen, additional, Stojkovic, Tanya, additional, Mori-Yoshimura, Madoka, additional, Bravver, Elena, additional, Pegoraro, Elena, additional, Mendell, Jerry R., additional, Bushby, Kate, additional, Straub, Volker, additional, and Diaz-Manera, Jordi, additional

Published
2020
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34. Importance of muscle biopsy to establish pathogenicity of DMD missense and splice variants

Author

Jones, Hannah F, primary, Bryen, Samantha J, additional, Waddell, Leigh B, additional, Bournazos, Adam, additional, Davis, Mark, additional, Farrar, Michelle A, additional, McLean, Catriona A, additional, Mowat, David R, additional, Sampaio, Hugo, additional, Woodcock, Ian R, additional, Ryan, Monique M, additional, Jones, Kristi J, additional, and Cooper, Sandra T, additional

Published
2019
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35. Teenage exercise is associated with earlier symptom onset in dysferlinopathy: a retrospective cohort study

Author

Moore, Ursula R, Jacobs, Marni, Fernandez-Torron, Roberto, Jang, Jiji, James, Meredith K, Mayhew, Anna, Rufibach, Laura, Mittal, Plavi, Eagle, Michelle, Cnaan, Avital, Carlier, Pierre G, Blamire, Andrew, Hilsden, Heather, Lochmüller, Hanns, Grieben, Ulrike, Spuler, Simone, Tesi Rocha, Carolina, Day, John W, Jones, Kristi J, Bharucha-Goebel, Diana X, Salort-Campana, Emmanuelle, Harms, Matthew, Pestronk, Alan, Krause, Sabine, Schreiber-Katz, Olivia, Walter, Maggie C, Paradas, Carmen, Hogrel, Jean-Yves, Stojkovic, Tanya, Takeda, Shin’ichi, Mori-Yoshimura, Madoka, Bravver, Elena, Sparks, Susan, Diaz-Manera, Jordi, Bello, Luca, Semplicini, Claudio, Pegoraro, Elena, Mendell, Jerry R, Bushby, Kate, and Straub, Volker

Subjects
muscular dystrophy, Adult, Male, Adolescent, Age Factors, PostScript, Middle Aged, Young Adult, Muscular Dystrophies, Limb-Girdle, Adolescent Behavior, Surveys and Questionnaires, Humans, Female, neuromuscular, Age of Onset, Function and Dysfunction of the Nervous System, Exercise, Retrospective Studies
Published
2018

38. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, Emily C., Jones, Kristi J., Donkervoort, Sandra, Charlton, Amanda, Brammah, Susan, Smith, John E., Ware, James S., Yau, Kyle S., Swanson, Lindsay C., Whiffin, Nicola, Peduto, Anthony J., Bournazos, Adam, Waddell, Leigh B., Farrar, Michelle A., Sampaio, Hugo A., Teoh, Hooi Ling, Lamont, Phillipa J., Mowat, David, Fitzsimons, Robin B., Corbett, Alastair J., Ryan, Monique M., O'Grady, Gina L., Sandaradura, Sarah A., Ghaoui, Roula, Joshi, Himanshu, Marshall, Jamie L., Nolan, Melinda A., Kaur, Simranpreet, Punetha, Jaya, Töpf, Ana, Harris, Elizabeth, Bakshi, Madhura, Genetti, Casie A., Marttila, Minttu, Werlauff, Ulla, Streichenberger, Nathalie, Pestronk, Alan, Mazanti, Ingrid, Pinner, Jason R., Vuillerot, Carole, Grosmann, Carla, Camacho, Ana, Mohassel, Payam, Leach, Meganne E., Foley, A. Reghan, Bharucha-Goebel, Diana, Collins, James, Connolly, Anne M., Gilbreath, Heather R., Iannaccone, Susan T., Castro, Diana, Cummings, Beryl B., Webster, Richard I., Lazaro, Leïla, Vissing, John, Coppens, Sandra, Deconinck, Nicolas, Luk, Ho Ming, Thomas, Neil H., Foulds, Nicola C., Illingworth, Marjorie A., Ellard, Sian, McLean, Catriona A., Phadke, Rahul, Ravenscroft, Gianina, Witting, Nanna, Hackman, Peter, Richard, Isabelle, Cooper, Sandra T., Kamsteeg, Erik Jan, Hoffman, Eric P., Bushby, Kate, Straub, Volker, Udd, Bjarne, Ferreiro, Ana, North, Kathryn N., Clarke, Nigel F., Lek, Monkol, Beggs, Alan H., Bönnemann, Carsten G., MacArthur, Daniel G., Granzier, Henk, Davis, Mark R., and Laing, Nigel G.

Subjects
Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
Abstract

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

40. Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Author

Koczkowska, Magdalena, primary, Callens, Tom, additional, Gomes, Alicia, additional, Sharp, Angela, additional, Chen, Yunjia, additional, Hicks, Alesha D., additional, Aylsworth, Arthur S., additional, Azizi, Amedeo A., additional, Basel, Donald G., additional, Bellus, Gary, additional, Bird, Lynne M., additional, Blazo, Maria A., additional, Burke, Leah W., additional, Cannon, Ashley, additional, Collins, Felicity, additional, DeFilippo, Colette, additional, Denayer, Ellen, additional, Digilio, Maria C., additional, Dills, Shelley K., additional, Dosa, Laura, additional, Greenwood, Robert S., additional, Griffis, Cristin, additional, Gupta, Punita, additional, Hachen, Rachel K., additional, Hernández-Chico, Concepción, additional, Janssens, Sandra, additional, Jones, Kristi J., additional, Jordan, Justin T., additional, Kannu, Peter, additional, Korf, Bruce R., additional, Lewis, Andrea M., additional, Listernick, Robert H., additional, Lonardo, Fortunato, additional, Mahoney, Maurice J., additional, Ojeda, Mayra Martinez, additional, McDonald, Marie T., additional, McDougall, Carey, additional, Mendelsohn, Nancy, additional, Miller, David T., additional, Mori, Mari, additional, Oostenbrink, Rianne, additional, Perreault, Sebastién, additional, Pierpont, Mary Ella, additional, Piscopo, Carmelo, additional, Pond, Dinel A., additional, Randolph, Linda M., additional, Rauen, Katherine A., additional, Rednam, Surya, additional, Rutledge, S. Lane, additional, Saletti, Veronica, additional, Schaefer, G. Bradley, additional, Schorry, Elizabeth K., additional, Scott, Daryl A., additional, Shugar, Andrea, additional, Siqveland, Elizabeth, additional, Starr, Lois J., additional, Syed, Ashraf, additional, Trapane, Pamela L., additional, Ullrich, Nicole J., additional, Wakefield, Emily G., additional, Walsh, Laurence E., additional, Wangler, Michael F., additional, Zackai, Elaine, additional, Claes, Kathleen B. M., additional, Wimmer, Katharina, additional, van Minkelen, Rick, additional, De Luca, Alessandro, additional, Martin, Yolanda, additional, Legius, Eric, additional, and Messiaen, Ludwine M., additional

Published
2018
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43. Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials

Author

Diaz-Manera, Jordi, primary, Fernandez-Torron, Roberto, additional, LLauger, Jaume, additional, James, Meredith K, additional, Mayhew, Anna, additional, Smith, Fiona E, additional, Moore, Ursula R, additional, Blamire, Andrew M, additional, Carlier, Pierre G, additional, Rufibach, Laura, additional, Mittal, Plavi, additional, Eagle, Michelle, additional, Jacobs, Marni, additional, Hodgson, Tim, additional, Wallace, Dorothy, additional, Ward, Louise, additional, Smith, Mark, additional, Stramare, Roberto, additional, Rampado, Alessandro, additional, Sato, Noriko, additional, Tamaru, Takeshi, additional, Harwick, Bruce, additional, Rico Gala, Susana, additional, Turk, Suna, additional, Coppenrath, Eva M, additional, Foster, Glenn, additional, Bendahan, David, additional, Le Fur, Yann, additional, Fricke, Stanley T, additional, Otero, Hansel, additional, Foster, Sheryl L, additional, Peduto, Anthony, additional, Sawyer, Anne Marie, additional, Hilsden, Heather, additional, Lochmuller, Hanns, additional, Grieben, Ulrike, additional, Spuler, Simone, additional, Tesi Rocha, Carolina, additional, Day, John W, additional, Jones, Kristi J, additional, Bharucha-Goebel, Diana X, additional, Salort-Campana, Emmanuelle, additional, Harms, Matthew, additional, Pestronk, Alan, additional, Krause, Sabine, additional, Schreiber-Katz, Olivia, additional, Walter, Maggie C, additional, Paradas, Carmen, additional, Hogrel, Jean-Yves, additional, Stojkovic, Tanya, additional, Takeda, Shin’ichi, additional, Mori-Yoshimura, Madoka, additional, Bravver, Elena, additional, Sparks, Susan, additional, Bello, Luca, additional, Semplicini, Claudio, additional, Pegoraro, Elena, additional, Mendell, Jerry R, additional, Bushby, Kate, additional, and Straub, Volker, additional

Published
2018
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44. Examining longitudinal functional changes in Dysferlinopathy: The JAIN Clinical Outcome Study (P5.429)

Author

Lowes, Linda, primary, James, Meredith, additional, Mayhew, Anna, additional, Alfano, Lindsay, additional, Jacobs, Marni, additional, Spuler, Simone, additional, Jones, Kristi J., additional, Day, John, additional, Bharucha-Goebel, Diana, additional, Campana-Salort, Emmanuelle, additional, Pestronk, Alan, additional, Walter, Maggie, additional, Paradas, Carmen, additional, Stojkovic, Tanya, additional, Mori-Yoshimura, Madoka, additional, Bravver, Elena, additional, Pegoraro, Elena, additional, Manera, Jordi Diaz, additional, Duong, Tina, additional, Rose, Kristy, additional, Mendell, Jerry, additional, Bushby, Kate, additional, and Straub, Volker, additional

Published
2018
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45. Nusinersen for SMA: expanded access programme

Author

Farrar, Michelle A, primary, Teoh, Hooi Ling, additional, Carey, Kate A, additional, Cairns, Anita, additional, Forbes, Robin, additional, Herbert, Karen, additional, Holland, Sandra, additional, Jones, Kristi J, additional, Menezes, Manoj P, additional, Morrison, Margot, additional, Munro, Kate, additional, Villano, Daniella, additional, Webster, Richard, additional, Woodcock, Ian R, additional, Yiu, Eppie M, additional, Sampaio, Hugo, additional, and Ryan, Monique M, additional

Published
2018
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46. Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Author

Koczkowska, Magdalena, primary, Chen, Yunjia, additional, Callens, Tom, additional, Gomes, Alicia, additional, Sharp, Angela, additional, Johnson, Sherrell, additional, Hsiao, Meng-Chang, additional, Chen, Zhenbin, additional, Balasubramanian, Meena, additional, Barnett, Christopher P., additional, Becker, Troy A., additional, Ben-Shachar, Shay, additional, Bertola, Debora R., additional, Blakeley, Jaishri O., additional, Burkitt-Wright, Emma M.M., additional, Callaway, Alison, additional, Crenshaw, Melissa, additional, Cunha, Karin S., additional, Cunningham, Mitch, additional, D’Agostino, Maria D., additional, Dahan, Karin, additional, De Luca, Alessandro, additional, Destrée, Anne, additional, Dhamija, Radhika, additional, Eoli, Marica, additional, Evans, D. Gareth R., additional, Galvin-Parton, Patricia, additional, George-Abraham, Jaya K., additional, Gripp, Karen W., additional, Guevara-Campos, Jose, additional, Hanchard, Neil A., additional, Hernández-Chico, Concepcion, additional, Immken, LaDonna, additional, Janssens, Sandra, additional, Jones, Kristi J., additional, Keena, Beth A., additional, Kochhar, Aaina, additional, Liebelt, Jan, additional, Martir-Negron, Arelis, additional, Mahoney, Maurice J., additional, Maystadt, Isabelle, additional, McDougall, Carey, additional, McEntagart, Meriel, additional, Mendelsohn, Nancy, additional, Miller, David T., additional, Mortier, Geert, additional, Morton, Jenny, additional, Pappas, John, additional, Plotkin, Scott R., additional, Pond, Dinel, additional, Rosenbaum, Kenneth, additional, Rubin, Karol, additional, Russell, Laura, additional, Rutledge, Lane S., additional, Saletti, Veronica, additional, Schonberg, Rhonda, additional, Schreiber, Allison, additional, Seidel, Meredith, additional, Siqveland, Elizabeth, additional, Stockton, David W., additional, Trevisson, Eva, additional, Ullrich, Nicole J., additional, Upadhyaya, Meena, additional, van Minkelen, Rick, additional, Verhelst, Helene, additional, Wallace, Margaret R., additional, Yap, Yoon-Sim, additional, Zackai, Elaine, additional, Zonana, Jonathan, additional, Zurcher, Vickie, additional, Claes, Kathleen, additional, Martin, Yolanda, additional, Korf, Bruce R., additional, Legius, Eric, additional, and Messiaen, Ludwine M., additional

Published
2018
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47. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

McDonald, Craig M, primary, Campbell, Craig, additional, Torricelli, Ricardo Erazo, additional, Finkel, Richard S, additional, Flanigan, Kevin M, additional, Goemans, Nathalie, additional, Heydemann, Peter, additional, Kaminska, Anna, additional, Kirschner, Janbernd, additional, Muntoni, Francesco, additional, Osorio, Andrés Nascimento, additional, Schara, Ulrike, additional, Sejersen, Thomas, additional, Shieh, Perry B, additional, Sweeney, H Lee, additional, Topaloglu, Haluk, additional, Tulinius, Már, additional, Vilchez, Juan J, additional, Voit, Thomas, additional, Wong, Brenda, additional, Elfring, Gary, additional, Kroger, Hans, additional, Luo, Xiaohui, additional, McIntosh, Joseph, additional, Ong, Tuyen, additional, Riebling, Peter, additional, Souza, Marcio, additional, Spiegel, Robert J, additional, Peltz, Stuart W, additional, Mercuri, Eugenio, additional, Alfano, Lindsay N, additional, Eagle, Michelle, additional, James, Meredith K, additional, Lowes, Linda, additional, Mayhew, Anna, additional, Mazzone, Elena S, additional, Nelson, Leslie, additional, Rose, Kristy J, additional, Abdel-Hamid, Hoda Z, additional, Apkon, Susan D, additional, Barohn, Richard J, additional, Bertini, Enrico, additional, Bloetzer, Clemens, additional, de Vaud, Lausanne Canton, additional, Butterfield, Russell J, additional, Chabrol, Brigitte, additional, Chae, Jong-Hee, additional, Jongno-gu, Daehak-ro, additional, Comi, Giacomi Pietro, additional, Darras, Basil T, additional, Dastgir, Jahannaz, additional, Desguerre, Isabelle, additional, Escobar, Raul G, additional, Finanger, Erika, additional, Guglieri, Michela, additional, Hughes, Imelda, additional, Iannaccone, Susan T, additional, Jones, Kristi J, additional, Karachunski, Peter, additional, Kudr, Martin, additional, Lotze, Timothy, additional, Mah, Jean K, additional, Mathews, Katherine, additional, Nevo, Yoram, additional, Parsons, Julie, additional, Péréon, Yann, additional, de Queiroz Campos Araujo, Alexandra Prufer, additional, Renfroe, J Ben, additional, de Resende, Maria Bernadete Dutra, additional, Ryan, Monique, additional, Selby, Kathryn, additional, Tennekoon, Gihan, additional, and Vita, Giuseppe, additional

Published
2017
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48. The Clinical Outcome Study for dysferlinopathy

Author

Harris, Elizabeth, Bladen, Catherine L., Mayhew, Anna, James, Meredith, Bettinson, Karen, Moore, Ursula, Smith, Fiona E., Rufibach, Laura, Cnaan, Avital, Bharucha-Goebel, Diana X., Blamire, Andrew M., Bravver, Elena, Carlier, Pierre G., Day, John W., Díaz-Manera, Jordi, Eagle, Michelle, Grieben, Ulrike, Harms, Matthew, Jones, Kristi J., Lochmüller, Hanns, Mendell, Jerry R., Mori-Yoshimura, Madoka, Paradas, Carmen, Pegoraro, Elena, Pestronk, Alan, Salort-Campana, Emmanuelle, Schreiber-Katz, Olivia, Semplicini, Claudio, Spuler, Simone, Stojkovic, Tanya, Straub, Volker, Takeda, Shin'ich, Rocha, Carolina Tesi, Walter, M.C., and Bushby, Kate

Subjects
Article
Abstract

Objective: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy. Methods: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments. Results: There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies. Conclusions: These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.

Published
2016

49. Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy

Author

Campbell, Craig, Barohn, Richard J, Bertini, Enrico, Chabrol, Brigitte, Comi, Giacomo Pietro, Darras, Basil T, Finkel, Richard S, Flanigan, Kevin M, Goemans, Nathalie, Iannaccone, Susan T, Jones, Kristi J, Kirschner, Janbernd, Mah, Jean K, Mathews, Katherine D, McDonald, Craig M, Mercuri, Eugenio, Nevo, Yoram, Péréon, Yann, Renfroe, J Ben, Ryan, Monique M, Sampson, Jacinda B, Schara, Ulrike, Sejersen, Thomas, Selby, Kathryn, Tulinius, Már, Vílchez, Juan J, Voit, Thomas, Wei, Lee-Jen, Wong, Brenda L, Elfring, Gary, Souza, Marcio, McIntosh, Joseph, Trifillis, Panayiota, Peltz, Stuart W, and Muntoni, Francesco

Abstract

Aim:Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Materials & methods:Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300–<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48. Results:Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2–34.1) m, p = 0.0473; ≥300–<400 m (n = 143), +43.9 (18.2–69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4–49.0) m, p = 0.0109. Conclusion:These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD ≥300–<400 m (the ambulatory transition phase), thereby informing future trial design.

Published
2020
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50. Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive <italic>TNNT3</italic> splice variant.

Author

Sandaradura, Sarah A., Bournazos, Adam, Mallawaarachchi, Amali, Cummings, Beryl B., Waddell, Leigh B., Jones, Kristi J., Troedson, Christopher, Sudarsanam, Annapurna, Nash, Benjamin M., Peters, Gregory B., Algar, Elizabeth M., MacArthur, Daniel G., North, Kathryn N., Brammah, Susan, Charlton, Amanda, Laing, Nigel G., Wilson, Meredith J., Davis, Mark R., and Cooper, Sandra T.

Abstract

Abstract: A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G > A, NM_006757.3:c.681+1G > A). TNNT3 encodes skeletal troponin‐Tfast and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon‐skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin‐Tfast protein with secondary loss of troponin‐Ifast. We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type‐2 fibers and deficiency of troponin‐Tfast. [ABSTRACT FROM AUTHOR]

Published
2018
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