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1. Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Author

Töpf, Ana, Cox, Dan, Zaharieva, Irina T., Di Leo, Valeria, Sarparanta, Jaakko, Jonson, Per Harald, Sealy, Ian M., Smolnikov, Andrei, White, Richard J., Vihola, Anna, Savarese, Marco, Merteroglu, Munise, Wali, Neha, Laricchia, Kristen M., Venturini, Cristina, Vroling, Bas, Stenton, Sarah L., Cummings, Beryl B., Harris, Elizabeth, Marini-Bettolo, Chiara, Diaz-Manera, Jordi, Henderson, Matt, Barresi, Rita, Duff, Jennifer, England, Eleina M., Patrick, Jane, Al-Husayni, Sundos, Biancalana, Valerie, Beggs, Alan H., Bodi, Istvan, Bommireddipalli, Shobhana, Bönnemann, Carsten G., Cairns, Anita, Chiew, Mei-Ting, Claeys, Kristl G., Cooper, Sandra T., Davis, Mark R., Donkervoort, Sandra, Erasmus, Corrie E., Fassad, Mahmoud R., Genetti, Casie A., Grosmann, Carla, Jungbluth, Heinz, Kamsteeg, Erik-Jan, Lornage, Xavière, Löscher, Wolfgang N., Malfatti, Edoardo, Manzur, Adnan, Martí, Pilar, Mongini, Tiziana E., Muelas, Nuria, Nishikawa, Atsuko, O’Donnell-Luria, Anne, Ogonuki, Narumi, O’Grady, Gina L., O’Heir, Emily, Paquay, Stéphanie, Phadke, Rahul, Pletcher, Beth A., Romero, Norma B., Schouten, Meyke, Shah, Snehal, Smuts, Izelle, Sznajer, Yves, Tasca, Giorgio, Taylor, Robert W., Tuite, Allysa, Van den Bergh, Peter, VanNoy, Grace, Voermans, Nicol C., Wanschitz, Julia V., Wraige, Elizabeth, Yoshimura, Kimihiko, Oates, Emily C., Nakagawa, Osamu, Nishino, Ichizo, Laporte, Jocelyn, Vilchez, Juan J., MacArthur, Daniel G., Sarkozy, Anna, Cordell, Heather J., Udd, Bjarne, Busch-Nentwich, Elisabeth M., Muntoni, Francesco, and Straub, Volker

Published
2024
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2. 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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3. 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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5. Genotype–phenotype correlations in recessive titinopathies

Author

Savarese, Marco, Vihola, Anna, Oates, Emily C., Barresi, Rita, Fiorillo, Chiara, Tasca, Giorgio, Jokela, Manu, Sarkozy, Anna, Luo, Sushan, Díaz-Manera, Jordi, Ehrstedt, Christoffer, Rojas-García, Ricardo, Sáenz, Amets, Muelas, Nuria, Lonardo, Fortunato, Fodstad, Heidi, Qureshi, Talha, Johari, Mridul, Välipakka, Salla, Luque, Helena, Petiot, Philippe, de Munain, Adolfo López, Pane, Marika, Mercuri, Eugenio, Torella, Annalaura, Nigro, Vincenzo, Astrea, Guja, Santorelli, Filippo Maria, Bruno, Claudio, Kuntzer, Thierry, Illa, Isabel, Vílchez, Juan J., Julien, Cedric, Ferreiro, Ana, Malandrini, Alessandro, Zhao, Chong-Bo, Casar-Borota, Olivera, Davis, Mark, Muntoni, Francesco, Hackman, Peter, and Udd, Bjarne

Published
2020
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6. DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies

Author

Johnson, Renee, primary, Otway, Robyn, additional, Chin, Ephrem, additional, Horvat, Claire, additional, Ohanian, Monique, additional, Wilcox, Jon A.L., additional, Su, Zheng, additional, Prestes, Priscilla, additional, Smolnikov, Andrei, additional, Soka, Magdalena, additional, Guo, Guanglan, additional, Rath, Emma, additional, Chakravorty, Samya, additional, Chrzanowski, Lukasz, additional, Hayward, Christopher S., additional, Keogh, Anne M., additional, Macdonald, Peter S., additional, Giannoulatou, Eleni, additional, Chang, Alex C.Y., additional, Oates, Emily C., additional, Charchar, Fadi, additional, Seidman, Jonathan G., additional, Seidman, Christine E., additional, Hegde, Madhuri, additional, and Fatkin, Diane, additional

Published
2023
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7. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or ‘classical’ congenital myopathy

Author

Zaharieva, Irina T., Thor, Michael G., Oates, Emily C., van Karnebeek, Clara, Hendson, Glenda, Blom, Eveline, Witting, Nanna, Rasmussen, Magnhild, Gabbett, Michael T., Ravenscroft, Gianina, Sframeli, Maria, Suetterlin, Karen, Sarkozy, Anna, D’Argenzio, Luigi, Hartley, Louise, Matthews, Emma, Pitt, Matthew, Vissing, John, Ballegaard, Martin, Krarup, Christian, Slørdahl, Andreas, Halvorsen, Hanne, Ye, Xin Cynthia, Zhang, Lin-Hua, Løkken, Nicoline, Werlauff, Ulla, Abdelsayed, Mena, Davis, Mark R., Feng, Lucy, Phadke, Rahul, Sewry, Caroline A., Morgan, Jennifer E., Laing, Nigel G., Vallance, Hilary, Ruben, Peter, Hanna, Michael G., Lewis, Suzanne, Kamsteeg, Erik-Jan, Männikkö, Roope, and Muntoni, Francesco

Published
2016
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8. Reply: The p.Ser107Leu in BICD2 is a mutation ‘hot spot’ causing distal spinal muscular atrophy

Author

Rossor, Alexander M., Oates, Emily C., Salter, Hannah K., Liu, Yang, Murphy, Sinead M., Schule, Rebecca, Gonzales, Michael A., Scoto, Mariacristina, Phadke, Rahul, Sewry, Caroline A., Houlden, Henry, Jordanova, Albena, Tournev, Iyailo, Chamova, Teodora, Litvinenko, Ivan, Zuchner, Stephan, Herrmann, David N., Blake, Julian, Sowden, Janet E., Acsadi, Gyuda, Rodriguez, Michael L., Menezes, Manoj P., Clarke, Nigel F., Auer Grumbach, Michaela, Bullock, Simon L., Muntoni, Francesco, Reilly, Mary M., and North, Kathryn N.

Published
2015
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9. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2

Author

Rossor, Alexander M., Oates, Emily C., Salter, Hannah K., Liu, Yang, Murphy, Sinead M., Schule, Rebecca, Gonzalez, Michael A., Scoto, Mariacristina, Phadke, Rahul, Sewry, Caroline A., Houlden, Henry, Jordanova, Albena, Tournev, Iyailo, Chamova, Teodora, Litvinenko, Ivan, Zuchner, Stephan, Herrmann, David N., Blake, Julian, Sowden, Janet E., Acsadi, Gyuda, Rodriguez, Michael L., Menezes, Manoj P., Clarke, Nigel F., Auer Grumbach, Michaela, Bullock, Simon L., Muntoni, Francesco, Reilly, Mary M., and North, Kathryn N.

Published
2015
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11. Making sense of missense variants in TTN-related congenital myopathies

Author

Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Oezdemir, Oezkan, Daimagueler, Hulya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joel, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma, Hanna, Michael, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schroeder, Rolf, Thiel, Christian, Reimann, Jens, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Dominguez-Gonzalez, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz, Gautel, Mathias, Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Oezdemir, Oezkan, Daimagueler, Hulya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joel, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma, Hanna, Michael, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schroeder, Rolf, Thiel, Christian, Reimann, Jens, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Dominguez-Gonzalez, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz, and Gautel, Mathias

Abstract

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Published
2021

12. Making sense of missense variants in TTN-related congenital myopathies

Author

UCL - (SLuc) Centre de référence neuromusculaire, Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Özdemir, Özkan, Daimagüler, Hülya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joël, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma, Hanna, Michael, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schröder, Rolf, Thiel, Christian, Reimann, Jens, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Domínguez-González, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz, Gautel, Mathias, UCL - (SLuc) Centre de référence neuromusculaire, Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Özdemir, Özkan, Daimagüler, Hülya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joël, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma, Hanna, Michael, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schröder, Rolf, Thiel, Christian, Reimann, Jens, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Domínguez-González, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz, and Gautel, Mathias

Abstract

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Published
2021

14. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

Author

Broad Institute of MIT and Harvard, Lincoln Laboratory, Cummings, Beryl, Marshall, Jamie L., Tukiainen, Taru, Lek, Monkol, Donkervoort, Sandra, Foley, A. Reghan, Bolduc, Veronique, Waddell, Leigh B., Sandaradura, Sarah A., O’Grady, Gina L., Estrella, Elicia, Reddy, Hemakumar M., Zhao, Fengmei, Weisburd, Ben, Karczewski, Konrad, O’Donnell-Luria, Anne H., Birnbaum, Daniel, Sarkozy, Anna, Hu, Ying, Gonorazky, Hernan, Claeys, Kristl, Joshi, Himanshu, Bournazos, Adam, Oates, Emily C., Ghaoui, Roula, Davis, Mark R., Laing, Nigel G., Topf, Ana, Kang, Peter B., Beggs, Alan H., North, Kathryn N., Straub, Volker, Dowling, James J., Muntoni, Francesco, Clarke, Nigel F., Cooper, Sandra T., Bönnemann, Carsten G., MacArthur, Daniel G., Broad Institute of MIT and Harvard, Lincoln Laboratory, Cummings, Beryl, Marshall, Jamie L., Tukiainen, Taru, Lek, Monkol, Donkervoort, Sandra, Foley, A. Reghan, Bolduc, Veronique, Waddell, Leigh B., Sandaradura, Sarah A., O’Grady, Gina L., Estrella, Elicia, Reddy, Hemakumar M., Zhao, Fengmei, Weisburd, Ben, Karczewski, Konrad, O’Donnell-Luria, Anne H., Birnbaum, Daniel, Sarkozy, Anna, Hu, Ying, Gonorazky, Hernan, Claeys, Kristl, Joshi, Himanshu, Bournazos, Adam, Oates, Emily C., Ghaoui, Roula, Davis, Mark R., Laing, Nigel G., Topf, Ana, Kang, Peter B., Beggs, Alan H., North, Kathryn N., Straub, Volker, Dowling, James J., Muntoni, Francesco, Clarke, Nigel F., Cooper, Sandra T., Bönnemann, Carsten G., and MacArthur, Daniel G.

Abstract

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches. 2017, National Institutes of Health (Grant GM096911), National Institute of General Medical Sciences (Grants F32GM115208 and 4T32GM007748)

Published
2020

15. 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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16. Making sense of missense variants in TTN-related congenital myopathies

Author

Rees, Martin, primary, Nikoopour, Roksana, additional, Fukuzawa, Atsushi, additional, Kho, Ay Lin, additional, Fernandez-Garcia, Miguel A., additional, Wraige, Elizabeth, additional, Bodi, Istvan, additional, Deshpande, Charu, additional, Özdemir, Özkan, additional, Daimagüler, Hülya-Sevcan, additional, Pfuhl, Mark, additional, Holt, Mark, additional, Brandmeier, Birgit, additional, Grover, Sarah, additional, Fluss, Joël, additional, Longman, Cheryl, additional, Farrugia, Maria Elena, additional, Matthews, Emma, additional, Hanna, Michael, additional, Muntoni, Francesco, additional, Sarkozy, Anna, additional, Phadke, Rahul, additional, Quinlivan, Ros, additional, Oates, Emily C., additional, Schröder, Rolf, additional, Thiel, Christian, additional, Reimann, Jens, additional, Voermans, Nicol, additional, Erasmus, Corrie, additional, Kamsteeg, Erik-Jan, additional, Konersman, Chaminda, additional, Grosmann, Carla, additional, McKee, Shane, additional, Tirupathi, Sandya, additional, Moore, Steven A., additional, Wilichowski, Ekkehard, additional, Hobbiebrunken, Elke, additional, Dekomien, Gabriele, additional, Richard, Isabelle, additional, Van den Bergh, Peter, additional, Domínguez-González, Cristina, additional, Cirak, Sebahattin, additional, Ferreiro, Ana, additional, Jungbluth, Heinz, additional, and Gautel, Mathias, additional

Published
2021
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19. Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy

Author

Bryen, Samantha J., primary, Oates, Emily C., additional, Evesson, Frances J., additional, Lu, Jessica K., additional, Waddell, Leigh B., additional, Joshi, Himanshu, additional, Ryan, Monique M., additional, Cummings, Beryl B., additional, McLean, Catriona A., additional, MacArthur, Daniel G., additional, Kornberg, Andrew J., additional, and Cooper, Sandra T., additional

Published
2020
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20. 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

21. Recessive MYH7-related myopathy in two families

Author

Beecroft, Sarah J., primary, van de Locht, Martijn, additional, de Winter, Josine M., additional, Ottenheijm, Coen A., additional, Sewry, Caroline A., additional, Mohammed, Shehla, additional, Ryan, Monique M., additional, Woodcock, Ian R., additional, Sanders, Lauren, additional, Gooding, Rebecca, additional, Davis, Mark R., additional, Oates, Emily C., additional, Laing, Nigel G., additional, Ravenscroft, Gianina, additional, McLean, Catriona A., additional, and Jungbluth, Heinz, additional

Published
2019
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22. 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., Laing, Nigel G., 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.

Abstract

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

23. Pathogenic deep intronic MTM1variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy

Author

Bryen, Samantha J., Oates, Emily C., Evesson, Frances J., Lu, Jessica K., Waddell, Leigh B., Joshi, Himanshu, Ryan, Monique M., Cummings, Beryl B., McLean, Catriona A., MacArthur, Daniel G., Kornberg, Andrew J., and Cooper, Sandra T.

Abstract

X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1variant NG_008199.1(NM_000252.2):c.1468-577A>G, which strengthened a cryptic 5' splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.

Published
2021
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24. Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases

Author

Punetha, Jaya, primary, Kesari, Akanchha, additional, Uapinyoying, Prech, additional, Giri, Mamta, additional, Clarke, Nigel F., additional, Waddell, Leigh B., additional, North, Kathryn N., additional, Ghaoui, Roula, additional, O’Grady, Gina L., additional, Oates, Emily C., additional, Sandaradura, Sarah A., additional, Bönnemann, Carsten G., additional, Donkervoort, Sandra, additional, Plotz, Paul H., additional, Smith, Edward C., additional, Tesi-Rocha, Carolina, additional, Bertorini, Tulio E., additional, Tarnopolsky, Mark A., additional, Reitter, Bernd, additional, Hausmanowa-Petrusewicz, Irena, additional, and Hoffman, Eric P., additional

Published
2016
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25. Diagnosis and etiology of congenital muscular dystrophy: We are halfway there

Author

O'Grady, Gina L., primary, Lek, Monkol, additional, Lamande, Shireen R., additional, Waddell, Leigh, additional, Oates, Emily C., additional, Punetha, Jaya, additional, Ghaoui, Roula, additional, Sandaradura, Sarah A., additional, Best, Heather, additional, Kaur, Simranpreet, additional, Davis, Mark, additional, Laing, Nigel G., additional, Muntoni, Francesco, additional, Hoffman, Eric, additional, MacArthur, Daniel G., additional, Clarke, Nigel F., additional, Cooper, Sandra, additional, and North, Kathryn, additional

Published
2016
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26. Loss-of-function mutations inSCN4Acause severe foetal hypokinesia or ‘classical’ congenital myopathy

Author

Zaharieva, Irina T., primary, Thor, Michael G., additional, Oates, Emily C., additional, van Karnebeek, Clara, additional, Hendson, Glenda, additional, Blom, Eveline, additional, Witting, Nanna, additional, Rasmussen, Magnhild, additional, Gabbett, Michael T., additional, Ravenscroft, Gianina, additional, Sframeli, Maria, additional, Suetterlin, Karen, additional, Sarkozy, Anna, additional, D’Argenzio, Luigi, additional, Hartley, Louise, additional, Matthews, Emma, additional, Pitt, Matthew, additional, Vissing, John, additional, Ballegaard, Martin, additional, Krarup, Christian, additional, Slørdahl, Andreas, additional, Halvorsen, Hanne, additional, Ye, Xin Cynthia, additional, Zhang, Lin-Hua, additional, Løkken, Nicoline, additional, Werlauff, Ulla, additional, Abdelsayed, Mena, additional, Davis, Mark R., additional, Feng, Lucy, additional, Phadke, Rahul, additional, Sewry, Caroline A., additional, Morgan, Jennifer E., additional, Laing, Nigel G., additional, Vallance, Hilary, additional, Ruben, Peter, additional, Hanna, Michael G., additional, Lewis, Suzanne, additional, Kamsteeg, Erik-Jan, additional, Männikkö, Roope, additional, and Muntoni, Francesco, additional

Published
2015
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27. Reply: The p.Ser107Leu inBICD2is a mutation ‘hot spot’ causing distal spinal muscular atrophy

Author

Rossor, Alexander M., primary, Oates, Emily C., additional, Salter, Hannah K., additional, Liu, Yang, additional, Murphy, Sinead M., additional, Schule, Rebecca, additional, Gonzales, Michael A., additional, Scoto, Mariacristina, additional, Phadke, Rahul, additional, Sewry, Caroline A., additional, Houlden, Henry, additional, Jordanova, Albena, additional, Tournev, Iyailo, additional, Chamova, Teodora, additional, Litvinenko, Ivan, additional, Zuchner, Stephan, additional, Herrmann, David N., additional, Blake, Julian, additional, Sowden, Janet E., additional, Acsadi, Gyuda, additional, Rodriguez, Michael L., additional, Menezes, Manoj P., additional, Clarke, Nigel F., additional, Auer Grumbach, Michaela, additional, Bullock, Simon L., additional, Muntoni, Francesco, additional, Reilly, Mary M., additional, and North, Kathryn N., additional

Published
2015
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28. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2

Author

Rossor, Alexander M., primary, Oates, Emily C., additional, Salter, Hannah K., additional, Liu, Yang, additional, Murphy, Sinead M., additional, Schule, Rebecca, additional, Gonzalez, Michael A., additional, Scoto, Mariacristina, additional, Phadke, Rahul, additional, Sewry, Caroline A., additional, Houlden, Henry, additional, Jordanova, Albena, additional, Tournev, Iyailo, additional, Chamova, Teodora, additional, Litvinenko, Ivan, additional, Zuchner, Stephan, additional, Herrmann, David N., additional, Blake, Julian, additional, Sowden, Janet E., additional, Acsadi, Gyuda, additional, Rodriguez, Michael L., additional, Menezes, Manoj P., additional, Clarke, Nigel F., additional, Auer Grumbach, Michaela, additional, Bullock, Simon L., additional, Muntoni, Francesco, additional, Reilly, Mary M., additional, and North, Kathryn N., additional

Published
2014
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29. Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine

Author

O'Grady, Gina L, primary, Best, Heather A, additional, Oates, Emily C, additional, Kaur, Simranpreet, additional, Charlton, Amanda, additional, Brammah, Susan, additional, Punetha, Jaya, additional, Kesari, Akanchha, additional, North, Kathryn N, additional, Ilkovski, Biljana, additional, Hoffman, Eric P, additional, and Clarke, Nigel F, additional

Published
2014
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31. Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia

Author

Oates, Emily C., primary, Rossor, Alexander M., additional, Hafezparast, Majid, additional, Gonzalez, Michael, additional, Speziani, Fiorella, additional, MacArthur, Daniel G., additional, Lek, Monkol, additional, Cottenie, Ellen, additional, Scoto, Mariacristina, additional, Foley, A. Reghan, additional, Hurles, Matthew, additional, Houlden, Henry, additional, Greensmith, Linda, additional, Auer-Grumbach, Michaela, additional, Pieber, Thomas R., additional, Strom, Tim M., additional, Schule, Rebecca, additional, Herrmann, David N., additional, Sowden, Janet E., additional, Acsadi, Gyula, additional, Menezes, Manoj P., additional, Clarke, Nigel F., additional, Züchner, Stephan, additional, Muntoni, Francesco, additional, North, Kathryn N., additional, and Reilly, Mary M., additional

Published
2013
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32. The p.Ser107Leu in BICD2 is a mutation 'hot spot' causing distal spinal muscular atrophy.

Author

Bansagi, Boglarka, Griffin, Helen, Ramesh, Venkateswaran, Duff, Jennifer, Pyle, Angela, Chinnery, Patrick F., Horvath, Rita, Rossor, Alexander M., Oates, Emily C., Salter, Hannah K., Yang Liu, Murphy, Sinead M., Schule, Rebecca, Gonzales, Michael A., Scoto, Mariacristina, Phadke, Rahul, Sewry, Caroline A., Houlden, Henry, Jordanova, Albena, and Tournev, Iyailo

Subjects
NERVE tissue proteins, SPINAL muscular atrophy
Published
2015
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33. Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.

Author

O'Grady, Gina L, Best, Heather A, Oates, Emily C, Kaur, Simranpreet, Charlton, Amanda, Brammah, Susan, Punetha, Jaya, Kesari, Akanchha, North, Kathryn N, Ilkovski, Biljana, Hoffman, Eric P, and Clarke, Nigel F

Subjects
MUSCULAR dystrophy genetics, NEUROMUSCULAR diseases, AUTOSOMAL recessive polycystic kidney, MISSENSE mutation, LONGITUDINAL ligaments, THERAPEUTICS
Abstract

Variants in ACTA1, which encodes α-skeletal actin, cause several congenital myopathies, most commonly nemaline myopathy. Autosomal recessive variants comprise approximately 10% of ACTA1 myopathy. All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth. Targeted next-generation sequencing in two brothers with congenital muscular dystrophy with rigid spine revealed homozygous missense variants in ACTA1. Skeletal α-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression. [ABSTRACT FROM AUTHOR]

Published
2015
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34. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

Author

Cummings, Beryl B., Marshall, Jamie L., Tukiainen, Taru, Lek, Monkol, Donkervoort, Sandra, Foley, A. Reghan, Bolduc, Veronique, Waddell, Leigh B., Sandaradura, Sarah A., O’Grady, Gina L., Estrella, Elicia, Reddy, Hemakumar M., Zhao, Fengmei, Weisburd, Ben, Karczewski, Konrad J., O’Donnell-Luria, Anne H., Birnbaum, Daniel, Sarkozy, Anna, Hu, Ying, Gonorazky, Hernan, Claeys, Kristl, Joshi, Himanshu, Bournazos, Adam, Oates, Emily C., Ghaoui, Roula, Davis, Mark R., Laing, Nigel G., Topf, Ana, Kang, Peter B., Beggs, Alan H., North, Kathryn N., Straub, Volker, Dowling, James J., Muntoni, Francesco, Clarke, Nigel F., Cooper, Sandra T., Bönnemann, Carsten G., and MacArthur, Daniel G.

Abstract

Transcriptome sequencing improves the diagnostic rate for Mendelian disease in patients for whom genetic analysis has not returned a diagnosis.

Published
2017
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35. Congenital Titinopathy: Comprehensive characterization and pathogenic insights.

Author

Oates EC, Jones KJ, Donkervoort S, Charlton A, Brammah S, Smith JE 3rd, Ware JS, Yau KS, Swanson LC, Whiffin N, Peduto AJ, Bournazos A, Waddell LB, Farrar MA, Sampaio HA, Teoh HL, Lamont PJ, Mowat D, Fitzsimons RB, Corbett AJ, Ryan MM, O'Grady GL, Sandaradura SA, Ghaoui R, Joshi H, Marshall JL, Nolan MA, Kaur S, Punetha J, Töpf A, Harris E, Bakshi M, Genetti CA, Marttila M, Werlauff U, Streichenberger N, Pestronk A, Mazanti I, Pinner JR, Vuillerot C, Grosmann C, Camacho A, Mohassel P, Leach ME, Foley AR, Bharucha-Goebel D, Collins J, Connolly AM, Gilbreath HR, Iannaccone ST, Castro D, Cummings BB, Webster RI, Lazaro L, Vissing J, Coppens S, Deconinck N, Luk HM, Thomas NH, Foulds NC, Illingworth MA, Ellard S, McLean CA, Phadke R, Ravenscroft G, Witting N, Hackman P, Richard I, Cooper ST, Kamsteeg EJ, Hoffman EP, Bushby K, Straub V, Udd B, Ferreiro A, North KN, Clarke NF, Lek M, Beggs AH, Bönnemann CG, MacArthur DG, Granzier H, Davis MR, and Laing NG

Subjects
Female, Humans, Male, Mutation genetics, Phenotype, Protein Isoforms genetics, Cardiomyopathy, Dilated congenital, Connectin genetics, Muscle Proteins genetics, Muscle, Skeletal pathology
Abstract

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., (© 2018 American Neurological Association.)

Published
2018
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