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1. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Published
2024
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3. Critical assessment of variant prioritization methods for rare disease diagnosis within the rare genomes project

Author

Stenton, Sarah L., O’Leary, Melanie C., Lemire, Gabrielle, VanNoy, Grace E., DiTroia, Stephanie, Ganesh, Vijay S., Groopman, Emily, O’Heir, Emily, Mangilog, Brian, Osei-Owusu, Ikeoluwa, Pais, Lynn S., Serrano, Jillian, Singer-Berk, Moriel, Weisburd, Ben, Wilson, Michael W., Austin-Tse, Christina, Abdelhakim, Marwa, Althagafi, Azza, Babbi, Giulia, Bellazzi, Riccardo, Bovo, Samuele, Carta, Maria Giulia, Casadio, Rita, Coenen, Pieter-Jan, De Paoli, Federica, Floris, Matteo, Gajapathy, Manavalan, Hoehndorf, Robert, Jacobsen, Julius O. B., Joseph, Thomas, Kamandula, Akash, Katsonis, Panagiotis, Kint, Cyrielle, Lichtarge, Olivier, Limongelli, Ivan, Lu, Yulan, Magni, Paolo, Mamidi, Tarun Karthik Kumar, Martelli, Pier Luigi, Mulargia, Marta, Nicora, Giovanna, Nykamp, Keith, Pejaver, Vikas, Peng, Yisu, Pham, Thi Hong Cam, Podda, Maurizio S., Rao, Aditya, Rizzo, Ettore, Saipradeep, Vangala G., Savojardo, Castrense, Schols, Peter, Shen, Yang, Sivadasan, Naveen, Smedley, Damian, Soru, Dorian, Srinivasan, Rajgopal, Sun, Yuanfei, Sunderam, Uma, Tan, Wuwei, Tiwari, Naina, Wang, Xiao, Wang, Yaqiong, Williams, Amanda, Worthey, Elizabeth A., Yin, Rujie, You, Yuning, Zeiberg, Daniel, Zucca, Susanna, Bakolitsa, Constantina, Brenner, Steven E., Fullerton, Stephanie M., Radivojac, Predrag, Rehm, Heidi L., and O’Donnell-Luria, Anne

Published
2024
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4. 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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5. Inferring compound heterozygosity from large-scale exome sequencing data

Author

Guo, Michael H., Francioli, Laurent C., Stenton, Sarah L., Goodrich, Julia K., Watts, Nicholas A., Singer-Berk, Moriel, Groopman, Emily, Darnowsky, Philip W., Solomonson, Matthew, Baxter, Samantha, Tiao, Grace, Neale, Benjamin M., Hirschhorn, Joel N., Rehm, Heidi L., Daly, Mark J., O’Donnell-Luria, Anne, Karczewski, Konrad J., MacArthur, Daniel G., and Samocha, Kaitlin E.

Published
2024
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6. Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort

Author

Dias, Kerith-Rae, Shrestha, Rupendra, Schofield, Deborah, Evans, Carey-Anne, O’Heir, Emily, Zhu, Ying, Zhang, Futao, Standen, Krystle, Weisburd, Ben, Stenton, Sarah L., Sanchis-Juan, Alba, Brand, Harrison, Talkowski, Michael E., Ma, Alan, Ghedia, Sondy, Wilson, Meredith, Sandaradura, Sarah A., Smith, Janine, Kamien, Benjamin, Turner, Anne, Bakshi, Madhura, Adès, Lesley C., Mowat, David, Regan, Matthew, McGillivray, George, Savarirayan, Ravi, White, Susan M., Tan, Tiong Yang, Stark, Zornitza, Brown, Natasha J., Pérez-Jurado, Luis A., Krzesinski, Emma, Hunter, Matthew F., Akesson, Lauren, Fennell, Andrew Paul, Yeung, Alison, Boughtwood, Tiffany, Ewans, Lisa J., Kerkhof, Jennifer, Lucas, Christopher, Carey, Louise, French, Hugh, Rapadas, Melissa, Stevanovski, Igor, Deveson, Ira W., Cliffe, Corrina, Elakis, George, Kirk, Edwin P., Dudding-Byth, Tracy, Fletcher, Janice, Walsh, Rebecca, Corbett, Mark A., Kroes, Thessa, Gecz, Jozef, Meldrum, Cliff, Cliffe, Simon, Wall, Meg, Lunke, Sebastian, North, Kathryn, Amor, David J., Field, Michael, Sadikovic, Bekim, Buckley, Michael F., O’Donnell-Luria, Anne, and Roscioli, Tony

Published
2024
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8. Genome Sequencing for Diagnosing Rare Diseases

Author

Wojcik, Monica H., primary, Lemire, Gabrielle, additional, Berger, Eva, additional, Zaki, Maha S., additional, Wissmann, Mariel, additional, Win, Wathone, additional, White, Susan M., additional, Weisburd, Ben, additional, Wieczorek, Dagmar, additional, Waddell, Leigh B., additional, Verboon, Jeffrey M., additional, VanNoy, Grace E., additional, Töpf, Ana, additional, Tan, Tiong Yang, additional, Syrbe, Steffen, additional, Strehlow, Vincent, additional, Straub, Volker, additional, Stenton, Sarah L., additional, Snow, Hana, additional, Singer-Berk, Moriel, additional, Silver, Josh, additional, Shril, Shirlee, additional, Seaby, Eleanor G., additional, Schneider, Ronen, additional, Sankaran, Vijay G., additional, Sanchis-Juan, Alba, additional, Russell, Kathryn A., additional, Reinson, Karit, additional, Ravenscroft, Gianina, additional, Radtke, Maximilian, additional, Popp, Denny, additional, Polster, Tilman, additional, Platzer, Konrad, additional, Pierce, Eric A., additional, Place, Emily M., additional, Pajusalu, Sander, additional, Pais, Lynn, additional, Õunap, Katrin, additional, Osei-Owusu, Ikeoluwa, additional, Opperman, Henry, additional, Okur, Volkan, additional, Oja, Kaisa Teele, additional, O’Leary, Melanie, additional, O’Heir, Emily, additional, Morel, Chantal F., additional, Merkenschlager, Andreas, additional, Marchant, Rhett G., additional, Mangilog, Brian E., additional, Madden, Jill A., additional, MacArthur, Daniel, additional, Lovgren, Alysia, additional, Lerner-Ellis, Jordan P., additional, Lin, Jasmine, additional, Laing, Nigel, additional, Hildebrandt, Friedhelm, additional, Hentschel, Julia, additional, Groopman, Emily, additional, Goodrich, Julia, additional, Gleeson, Joseph G., additional, Ghaoui, Roula, additional, Genetti, Casie A., additional, Gburek-Augustat, Janina, additional, Gazda, Hanna T., additional, Ganesh, Vijay S., additional, Ganapathi, Mythily, additional, Gallacher, Lyndon, additional, Fu, Jack M., additional, Evangelista, Emily, additional, England, Eleina, additional, Donkervoort, Sandra, additional, DiTroia, Stephanie, additional, Cooper, Sandra T., additional, Chung, Wendy K., additional, Christodoulou, John, additional, Chao, Katherine R., additional, Cato, Liam D., additional, Bujakowska, Kinga M., additional, Bryen, Samantha J., additional, Brand, Harrison, additional, Bönnemann, Carsten G., additional, Beggs, Alan H., additional, Baxter, Samantha M., additional, Bartolomaeus, Tobias, additional, Agrawal, Pankaj B., additional, Talkowski, Michael, additional, Austin-Tse, Christina, additional, Abou Jamra, Rami, additional, Rehm, Heidi L., additional, and O’Donnell-Luria, Anne, additional

Published
2024
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9. Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency

Author

Baiko, Sergey, Serna Higuita, Lina Maria, Schaefer, Franz, Trautmann, Agnes, Tabatabaeifar, Mansoureh, Gheissari, Alaleh, Hooman, Nakysa, Benetti, Elisa, Emma, Francesco, Nigmatullina, Nazym, Lipska-Ziętkiewicz, Beata S., Bałasz-Chmielewska, Irena, Tkaczyk, Marcin, Stańczyk, Małgorzata, Borzecka, Halina, Tsygin, Alexey N., Prikhodina, Larisa, Bogdanovic, Radovan, Anarat, Ali, Ozaltin, Fatih, Mir, Sevgi, Fomina, Svitlana, Klopstock, Thomas, Prokisch, Holger, Kornblum, Cornelia, Xu, Hong, Shen, Qian, Rao, Jia, Liu, Cui-Hua, Sun, Shu-Zhen, Deng, Fang, Dong, Yang, Wang, Xiao-Wen, Luan, Jiang-Wei, Drovandi, Stefania, Gulhan, Bora, Boyer, Olivia, Riedhammer, Korbinian M., Heemann, Uwe, Hoefele, Julia, Stenton, Sarah L., Ng, Kar-Hui, Aurelle, Manon, Schreuder, Michiel F., Jankowski, Maciej, Mao, Jianhua, Feng, Chunyue, Liu, Cuihua, Sun, Shuzhen, Wang, Xiaowen, Clavé, Stéphanie, Fila, Marc, Durkan, Anne M., Levart, Tanja Kersnik, Dursun, Ismail, Esfandiar, Nasrin, Haas, Dorothea, Bjerre, Anna, Benz, Marcus R., Talebi, Saeed, and Ariceta, Gema

Published
2022
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10. Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy

Author

Baiko, Sergey, Serna Higuita, Lina Maria, Schaefer, Franz, Trautmann, Agnes, Tabatabaeifar, Mansoureh, Gheissari, Alaleh, Hooman, Nakysa, Benetti, Elisa, Emma, Francesco, Nigmatullina, Nazym, Lipska-Ziętkiewicz, Beata S., Bałasz-Chmielewska, Irena, Tkaczyk, Marcin, Stańczyk, Małgorzata, Borzecka, Halina, Tsygin, Alexey N., Prikhodina, Larisa, Bogdanovic, Radovan, Anarat, Ali, Ozaltin, Fatih, Mir, Sevgi, Fomina, Svitlana, Klopstock, Thomas, Prokisch, Holger, Kornblum, Cornelia, Xu, Hong, Shen, Qian, Rao, Jia, Liu, Cui-Hua, Sun, Shu-Zhen, Deng, Fang, Dong, Yang, Wang, Xiao-Wen, Luan, Jiang-Wei, Drovandi, Stefania, Gulhan, Bora, Boyer, Olivia, Ziętkiewicz, Szymon, Riedhammer, Korbinian M., Heemann, Uwe, Hoefele, Julia, Stenton, Sarah L., Ng, Kar-Hui, Aurelle, Manon, Schijvens, Anne M., Jankowski, Maciej, Mao, Jianhua, Feng, Chunyue, Rousset-Rouviere, Caroline, Fila, Marc, Durkan, Anne M., Levart, Tanja Kersnik, Dursun, Ismail, Esfandiar, Nasrin, Haas, Dorothea, Bjerre, Anna, Benz, Marcus R., Talebi, Saeed, and Ariceta, Gema

Published
2022
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11. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A., Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H., Alston, Charlotte L., Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes, Hayflick, Susan J., Hempel, Maja, Itkis, Yulia S., Kishita, Yoshihito, Klopstock, Thomas, Krylova, Tatiana D., Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F., Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, Schwarzmayr, Thomas, Smet, Joél, Staufner, Christian, Stenton, Sarah L., Strom, Tim M., Terrile, Caterina, Tort, Frederic, Van Coster, Rudy, Vanlander, Arnaud, Wagner, Matias, Xu, Manting, Fang, Fang, Ghezzi, Daniele, Mayr, Johannes A., Piekutowska-Abramczuk, Dorota, Ribes, Antonia, Rötig, Agnès, Taylor, Robert W., Wortmann, Saskia B., Murayama, Kei, Meitinger, Thomas, Gagneur, Julien, and Prokisch, Holger

Published
2022
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12. Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant

Author

Blickhäuser, Beryll, primary, Stenton, Sarah L, additional, Neuhofer, Christiane M, additional, Floride, Elisa, additional, Nesbitt, Victoria, additional, Fratter, Carl, additional, Koch, Johannes, additional, Kauffmann, Birgit, additional, Catarino, Claudia, additional, Schlieben, Lea Dewi, additional, Kopajtich, Robert, additional, Carelli, Valerio, additional, Sadun, Alfredo A, additional, McFarland, Robert, additional, Fang, Fang, additional, La Morgia, Chiara, additional, Paquay, Stéphanie, additional, Nassogne, Marie Cécile, additional, Ghezzi, Daniele, additional, Lamperti, Costanza, additional, Wortmann, Saskia, additional, Poulton, Jo, additional, Klopstock, Thomas, additional, and Prokisch, Holger, additional

Published
2024
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13. Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations

Author

Biesecker, Leslie G., Harrison, Steven M., Tayoun, Ahmad A., Berg, Jonathan S., Brenner, Steven E., Cutting, Garry R., Ellard, Sian, Greenblatt, Marc S., Kang, Peter, Karbassi, Izabela, Karchin, Rachel, Mester, Jessica, O’Donnell-Luria, Anne, Pesaran, Tina, Plon, Sharon E., Rehm, Heidi L., Strande, Natasha T., Tavtigian, Sean V., Topper, Scott, Stenton, Sarah L., Pejaver, Vikas, Bergquist, Timothy, Byrne, Alicia B., Nadeau, Emily A.W., and Radivojac, Predrag

Published
2024
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15. Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis

Author

Wojcik, Monica H, primary, Lemire, Gabrielle, additional, Zaki, Maha S, additional, Wissmann, Mariel, additional, Win, Wathone, additional, White, Sue, additional, Weisburd, Ben, additional, Waddell, Leigh B, additional, Verboon, Jeffrey M, additional, VanNoy, Grace E, additional, Topf, Ana, additional, Tan, Tiong Yang, additional, Straub, Volker, additional, Stenton, Sarah L, additional, Snow, Hana, additional, Singer-Berk, Moriel, additional, Silver, Josh, additional, Shril, Shirlee, additional, Seaby, Eleanor G, additional, Schneider, Ronen, additional, Sankaran, Vijay G, additional, Sanchis-Juan, Alba, additional, Russell, Kathryn A, additional, Reinson, Karit, additional, Ravenscroft, Gina, additional, Pierce, Eric A, additional, Place, Emily M, additional, Pajusalu, Sander, additional, Pais, Lynn, additional, Ounap, Katrin, additional, Osei-Owusu, Ikeoluwa, additional, Okur, Volkan, additional, Oja, Kaisa Teele, additional, OLeary, Melanie, additional, OHeir, Emily, additional, Morel, Chantal, additional, Marchant, Rhett G, additional, Mangilog, Brian E, additional, Madden, Jill A, additional, MacArthur, Daniel, additional, Lovgren, Alysia, additional, Lerner-Ellis, Jordan P, additional, Lin, Jasmine, additional, Laing, Nigel, additional, Hildebrandt, Friedhelm, additional, Groopman, Emily, additional, Goodrich, Julia, additional, Gleeson, Joseph G, additional, Ghaoui, Roula, additional, Genetti, Casie A, additional, Gazda, Hanna, additional, Ganesh, Vijay S, additional, Ganapathi, Mythily, additional, Gallacher, Lyndon, additional, Fu, Jack, additional, Evangelista, Emily, additional, England, Eleina, additional, Donkervoort, Sandra, additional, DiTroia, Stephanie, additional, Cooper, Sandra T, additional, Chung, Wendy K, additional, Christodoulou, John, additional, Chao, Katherine R, additional, Cato, Liam D, additional, Bujakowska, Kinga M, additional, Bryen, Samantha J, additional, Brand, Harrison, additional, Bonnemann, Carsten, additional, Beggs, Alan H, additional, Baxter, Samantha M, additional, Agrawal, Pankaj B, additional, Talkowski, Michael, additional, Austin-Tse, Christina, additional, Rehm, Heidi L, additional, and ODonnell-Luria, Anne, additional

Published
2023
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16. Critical assessment of variant prioritization methods for rare disease diagnosis within the Rare Genomes Project

Author

Stenton, Sarah L., primary, O’Leary, Melanie, additional, Lemire, Gabrielle, additional, VanNoy, Grace E., additional, DiTroia, Stephanie, additional, Ganesh, Vijay S., additional, Groopman, Emily, additional, O’Heir, Emily, additional, Mangilog, Brian, additional, Osei-Owusu, Ikeoluwa, additional, Pais, Lynn S., additional, Serrano, Jillian, additional, Singer-Berk, Moriel, additional, Weisburd, Ben, additional, Wilson, Michael, additional, Austin-Tse, Christina, additional, Abdelhakim, Marwa, additional, Althagafi, Azza, additional, Babbi, Giulia, additional, Bellazzi, Riccardo, additional, Bovo, Samuele, additional, Carta, Maria Giulia, additional, Casadio, Rita, additional, Coenen, Pieter-Jan, additional, De Paoli, Federica, additional, Floris, Matteo, additional, Gajapathy, Manavalan, additional, Hoehndorf, Robert, additional, Jacobsen, Julius O.B., additional, Joseph, Thomas, additional, Kamandula, Akash, additional, Katsonis, Panagiotis, additional, Kint, Cyrielle, additional, Lichtarge, Olivier, additional, Limongelli, Ivan, additional, Lu, Yulan, additional, Magni, Paolo, additional, Mamidi, Tarun Karthik Kumar, additional, Martelli, Pier Luigi, additional, Mulargia, Marta, additional, Nicora, Giovanna, additional, Nykamp, Keith, additional, Pejaver, Vikas, additional, Peng, Yisu, additional, Pham, Thi Hong Cam, additional, Podda, Maurizio S., additional, Rao, Aditya, additional, Rizzo, Ettore, additional, Saipradeep, Vangala G, additional, Savojardo, Castrense, additional, Schols, Peter, additional, Shen, Yang, additional, Sivadasan, Naveen, additional, Smedley, Damian, additional, Soru, Dorian, additional, Srinivasan, Rajgopal, additional, Sun, Yuanfei, additional, Sunderam, Uma, additional, Tan, Wuwei, additional, Tiwari, Naina, additional, Wang, Xiao, additional, Wang, Yaqiong, additional, Williams, Amanda, additional, Worthey, Elizabeth A., additional, Yin, Rujie, additional, You, Yuning, additional, Zeiberg, Daniel, additional, Zucca, Susanna, additional, Bakolitsa, Constantina, additional, Brenner, Steven E., additional, Fullerton, Stephanie M, additional, Radivojac, Predrag, additional, Rehm, Heidi L., additional, and O’Donnell-Luria, Anne, additional

Published
2023
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17. Inferring compound heterozygosity from large-scale exome sequencing data

Author

Guo, Michael H., Francioli, Laurent C., Stenton, Sarah L., Goodrich, Julia K., Watts, Nicholas A., Singer-Berk, Moriel, Groopman, Emily, Darnowsky, Philip W., Solomonson, Matthew, Baxter, Samantha, Tiao, Grace, Neale, Benjamin M., Hirschhorn, Joel N., Rehm, Heidi L., Daly, Mark J., O’Donnell-Luria, Anne, Karczewski, Konrad J., MacArthur, Daniel G., and Samocha, Kaitlin E.

Subjects
Article
Abstract

Severe recessive diseases arise when both the maternal and the paternal copies of a gene carry, or are impacted by, a damaging genetic variant in the affected individual. When a patient carries two different potentially causal variants, accurate diagnosis requires determining that these two variants occur on different copies of the chromosome (i.e., are in trans ) rather than on the same copy (i.e., in cis ). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. We developed a strategy for inferring phase for rare variant pairs within genes, leveraging haplotype patterns observed in exome sequencing data from the Genome Aggregation Database (gnomAD v2, n=125,748). When applied to trio data where phase is known, our approach estimates phase with high accuracy, even for very rare variants (frequency

Published
2023

18. Impaired complex I repair causes recessive Leber's hereditary optic neuropathy

Author

Stenton, Sarah L., Sheremet, Natalia L., Catarino, Claudia B., Andreeva, Natalia A., Assouline, Zahra, Barboni, Piero, Bare, Ortal, Berutti, Riccardo, Bychkov, Igor, and Caporali, Leonardo

Subjects
Optic atrophy -- Genetic aspects -- Causes of, NADH dehydrogenase -- Physiological aspects -- Health aspects, Health care industry
Abstract

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits., Introduction Leber's hereditary optic neuropathy (LHON, OMIM:535000) was first noted by Von Graefe in 1858 (1) and was formally described as a clinical entity bearing his name by Leber in [...]

Published
2021
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19. De novo variants in the RNU4-2snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2as a syndromic NDD gene. RNU4-2encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2is highly expressed in the developing human brain, in contrast to RNU4-1and other U4 homologues. Using RNA sequencing, we show how 5′ splice-site use is systematically disrupted in individuals with RNU4-2variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Published
2024
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20. The phenotypic spectrum of COX20-associated mitochondrial disorder

Author

Ban, Rui, primary, Kopajtich, Robert, additional, Lv, Junlan, additional, Stenton, Sarah L, additional, Shimura, Masaru, additional, Wang, Zhaoxia, additional, Yuan, Yun, additional, Wang, Junling, additional, Han, Xiaodi, additional, Liu, Zhimei, additional, Shi, Qiang, additional, Pu, Chuanqiang, additional, Prokisch, Holger, additional, Fang, Fang, additional, and Elstner, Matthias, additional

Published
2022
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21. Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency

Author

Drovandi, Stefania, primary, Lipska-Ziętkiewicz, Beata S., additional, Ozaltin, Fatih, additional, Emma, Francesco, additional, Gulhan, Bora, additional, Boyer, Olivia, additional, Trautmann, Agnes, additional, Xu, Hong, additional, Shen, Qian, additional, Rao, Jia, additional, Riedhammer, Korbinian M., additional, Heemann, Uwe, additional, Hoefele, Julia, additional, Stenton, Sarah L., additional, Tsygin, Alexey N., additional, Ng, Kar-Hui, additional, Fomina, Svitlana, additional, Benetti, Elisa, additional, Aurelle, Manon, additional, Prikhodina, Larisa, additional, Schreuder, Michiel F., additional, Tabatabaeifar, Mansoureh, additional, Jankowski, Maciej, additional, Baiko, Sergey, additional, Mao, Jianhua, additional, Feng, Chunyue, additional, Liu, Cuihua, additional, Sun, Shuzhen, additional, Deng, Fang, additional, Wang, Xiaowen, additional, Clavé, Stéphanie, additional, Stańczyk, Małgorzata, additional, Bałasz-Chmielewska, Irena, additional, Fila, Marc, additional, Durkan, Anne M., additional, Levart, Tanja Kersnik, additional, Dursun, Ismail, additional, Esfandiar, Nasrin, additional, Haas, Dorothea, additional, Bjerre, Anna, additional, Anarat, Ali, additional, Benz, Marcus R., additional, Talebi, Saeed, additional, Hooman, Nakysa, additional, Ariceta, Gema, additional, Schaefer, Franz, additional, Serna Higuita, Lina Maria, additional, Gheissari, Alaleh, additional, Nigmatullina, Nazym, additional, Tkaczyk, Marcin, additional, Borzecka, Halina, additional, Bogdanovic, Radovan, additional, Mir, Sevgi, additional, Klopstock, Thomas, additional, Prokisch, Holger, additional, Kornblum, Cornelia, additional, Liu, Cui-Hua, additional, Sun, Shu-Zhen, additional, Dong, Yang, additional, Wang, Xiao-Wen, additional, and Luan, Jiang-Wei, additional

Published
2022
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22. Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy

Author

Drovandi, Stefania, primary, Lipska-Ziętkiewicz, Beata S., additional, Ozaltin, Fatih, additional, Emma, Francesco, additional, Gulhan, Bora, additional, Boyer, Olivia, additional, Trautmann, Agnes, additional, Ziętkiewicz, Szymon, additional, Xu, Hong, additional, Shen, Qian, additional, Rao, Jia, additional, Riedhammer, Korbinian M., additional, Heemann, Uwe, additional, Hoefele, Julia, additional, Stenton, Sarah L., additional, Tsygin, Alexey N., additional, Ng, Kar-Hui, additional, Fomina, Svitlana, additional, Benetti, Elisa, additional, Aurelle, Manon, additional, Prikhodina, Larisa, additional, Schijvens, Anne M., additional, Tabatabaeifar, Mansoureh, additional, Jankowski, Maciej, additional, Baiko, Sergey, additional, Mao, Jianhua, additional, Feng, Chunyue, additional, Deng, Fang, additional, Rousset-Rouviere, Caroline, additional, Stańczyk, Małgorzata, additional, Bałasz-Chmielewska, Irena, additional, Fila, Marc, additional, Durkan, Anne M., additional, Levart, Tanja Kersnik, additional, Dursun, Ismail, additional, Esfandiar, Nasrin, additional, Haas, Dorothea, additional, Bjerre, Anna, additional, Anarat, Ali, additional, Benz, Marcus R., additional, Talebi, Saeed, additional, Hooman, Nakysa, additional, Ariceta, Gema, additional, Schaefer, Franz, additional, Serna Higuita, Lina Maria, additional, Gheissari, Alaleh, additional, Nigmatullina, Nazym, additional, Tkaczyk, Marcin, additional, Borzecka, Halina, additional, Bogdanovic, Radovan, additional, Mir, Sevgi, additional, Klopstock, Thomas, additional, Prokisch, Holger, additional, Kornblum, Cornelia, additional, Liu, Cui-Hua, additional, Sun, Shu-Zhen, additional, Dong, Yang, additional, Wang, Xiao-Wen, additional, and Luan, Jiang-Wei, additional

Published
2022
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24. Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital

Author

Stenton, Sarah L., primary, Zou, Ying, additional, Cheng, Hua, additional, Liu, Zhimei, additional, Wang, Junling, additional, Shen, Danmin, additional, Jin, Hong, additional, Ding, Changhong, additional, Tang, Xiaolu, additional, Sun, Suzhen, additional, Han, Hong, additional, Ma, Yanli, additional, Zhang, Weihua, additional, Jin, Ruifeng, additional, Wang, Hua, additional, Sun, Dan, additional, Lv, Jun Lan, additional, Prokisch, Holger, additional, and Fang, Fang, additional

Published
2022
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25. Additional file 2 of Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A., Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H., Alston, Charlotte L., Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes, Hayflick, Susan J., Hempel, Maja, Itkis, Yulia S., Kishita, Yoshihito, Klopstock, Thomas, Krylova, Tatiana D., Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F., Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, Schwarzmayr, Thomas, Smet, Joél, Staufner, Christian, Stenton, Sarah L., Strom, Tim M., Terrile, Caterina, Tort, Frederic, Van Coster, Rudy, Vanlander, Arnaud, Wagner, Matias, Xu, Manting, Fang, Fang, Ghezzi, Daniele, Mayr, Johannes A., Piekutowska-Abramczuk, Dorota, Ribes, Antonia, Rötig, Agnès, Taylor, Robert W., Wortmann, Saskia B., Murayama, Kei, Meitinger, Thomas, Gagneur, Julien, and Prokisch, Holger

Subjects
parasitic diseases, population characteristics, geographic locations, health care economics and organizations
Abstract

Additional file 2: Fig. S1. Overview of the study. Fig. S2. Quality control. Fig. S3. DNA-RNA sample matching. Fig. S4. Aberrant events per sample. Fig. S5. Rare variants among expression outliers. Fig. S6. Power analysis of overexpression outliers. Fig. S7. Power analysis of underexpression outliers with respect to biological coefficient of variation. Fig. S8. Cases with many mtDNA expression outliers. Fig. S9. Rare variants among splicing outliers. Fig. S10. Splicing prediction algorithms evaluation. Fig. S11. Complex pattern of aberrant splicing. Fig. S12. Analysis of variants called by RNA-seq. Fig. S13. Rare variants leading to outliers. Fig. S14. Diagnostic rate across cohorts.

Published
2022
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26. DNAJC30 defect: a frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome

Author

Stenton, Sarah L., primary, Tesarova, Marketa, additional, Sheremet, Natalia L., additional, Catarino, Claudia B., additional, Carelli, Valerio, additional, Ciara, Elżbieta, additional, Curry, Kathryn, additional, Engvall, Martin, additional, Fleming, Leah R., additional, Freisinger, Peter, additional, Iwanicka-Pronicka, Katarzyna, additional, Jurkiewicz, Elżbieta, additional, Klopstock, Thomas, additional, Koenig, Mary K., additional, Kolářová, Hana, additional, Kousal, Bohdan, additional, Krylova, Tatiana, additional, La Morgia, Chiara, additional, Nosková, Lenka, additional, Piekutowska-Abramczuk, Dorota, additional, Russo, Sam N., additional, Stránecký, Viktor, additional, Tóthová, Iveta, additional, Träisk, Frank, additional, and Prokisch, Holger, additional

Published
2022
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27. PRIMARY COQ10 DEFICIENCY: CLINICAL SPECTRUM AND GENOTYPE-PHENOTYPE CORRELATIONS

Author

GÜLHAN, BORA, Manon, Aurelle, Prikhodina, Larisa, Jankowski, Maciej, Rao, Jia, Shen, Qian, Trautmann, Agnes, Boyer, Olivia, Hooman, Nakysa, Xu, Hong, Talebi, Saeed, Rousset-rouviere, Caroline, Wang, Xiaowen, Deng, Fang, Sun, Shuzhen, Liu, Cuihua, Feng, Chunyue, Ng, Kar-Hui, Tsygin, Alexej, Benz, Marcus, Mao, Jianhua, Baiko, Sergey, Emma, Francesco, ÖZALTIN, FATİH, Lipska-zietkiewicz, Beata S., Drovandi, Stefania, Anarat, Ali, Bjerre, Anna, Haas, Dorothea, Esfandiar, Nasrin, Hoefele, Julia, Schaefer, Franz, Riedhammer, Korbinian M., Ariceta, Gema, Stenton, Sarah L., Fomina, Svitlana, Benetti, Elisa, Schijvens, Anne M., Tabatabaeifar, Monsoureh, Stanczyk, Malgorzata, Balasz-Chmielewska, Irena, Fila, Marc, Durkan, Anne M., Levart, Tanja Kersnik, and DURSUN, İSMAİL

Published
2021

28. Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes

Author

Stenton, Sarah L., primary, Shimura, Masaru, additional, Piekutowska-Abramczuk, Dorota, additional, Freisinger, Peter, additional, Distelmaier, Felix, additional, Mayr, Johannes A., additional, Makowski, Christine, additional, Büchner, Boriana, additional, Alhaddad, Bader, additional, Alston, Charlotte L., additional, Ardissone, Anna, additional, Ban, Rui, additional, Barić, Ivo, additional, Berutti, Riccardo, additional, Brunet, Theresa, additional, Ciara, Elżbieta, additional, Deen, Dasha, additional, Gagneur, Julien, additional, Ghezzi, Daniele, additional, Gusic, Mirjana, additional, Haack, Tobias B., additional, Hempel, Maja, additional, Husain, Ralf A., additional, Karall, Daniela, additional, Kölker, Stefan, additional, Kotzaeridou, Urania, additional, Klopstock, Thomas, additional, Kopajtich, Robert, additional, Konstantopoulou, Vassiliki, additional, Liez, Steffen, additional, Lenz, Dominic, additional, Lim, Albert Z., additional, Mandel, Hanna, additional, McFarland, Robert, additional, Müller-Felber, Wolfgang, additional, Muñoz-Pujol, Gerard, additional, Ohtake, Akira, additional, Okazaki, Yasushi, additional, Olsen, Rikke, additional, Pronicka, Ewa, additional, Pyle, Angela, additional, Ribes, Antonia, additional, Rokicki, Dariusz, additional, Santer, René, additional, Schiff, Manuel, additional, Schuelke, Markus, additional, Smirnov, Dmitrii, additional, Sperl, Wolfgang, additional, Strom, Tim, additional, Tort, Frederic, additional, Tsygankova, Polina, additional, van Coster, Rudy, additional, Verloo, Patrick, additional, von Kleist-Retzow, Jürgen-Christoph, additional, Wilichowski, Ekkehard, additional, Wolstein, Tekla, additional, Xu, Manting, additional, Yépez, Vicente, additional, Zech, Michael, additional, Wortmann, Saskia, additional, Wagner, Matias, additional, Lamperti, Costanza, additional, Taylor, Robert W., additional, Fang, Fang, additional, Rötig, Agnés, additional, Murayama, Kei, additional, Meitinger, Thomas, additional, and Prokisch, Holger, additional

Published
2021
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29. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A., primary, Gusic, Mirjana, additional, Kopajtich, Robert, additional, Mertes, Christian, additional, Smith, Nicholas H., additional, Alston, Charlotte L., additional, Ban, Rui, additional, Beblo, Skadi, additional, Berutti, Riccardo, additional, Blessing, Holger, additional, Ciara, Elżbieta, additional, Distelmaier, Felix, additional, Freisinger, Peter, additional, Häberle, Johannes, additional, Hayflick, Susan J., additional, Hempel, Maja, additional, Itkis, Yulia S., additional, Kishita, Yoshihito, additional, Klopstock, Thomas, additional, Krylova, Tatiana D., additional, Lamperti, Costanza, additional, Lenz, Dominic, additional, Makowski, Christine C., additional, Mosegaard, Signe, additional, Müller, Michaela F., additional, Muñoz-Pujol, Gerard, additional, Nadel, Agnieszka, additional, Ohtake, Akira, additional, Okazaki, Yasushi, additional, Procopio, Elena, additional, Schwarzmayr, Thomas, additional, Smet, Joél, additional, Staufner, Christian, additional, Stenton, Sarah L., additional, Strom, Tim M., additional, Terrile, Caterina, additional, Tort, Frederic, additional, Van Coster, Rudy, additional, Vanlander, Arnaud, additional, Wagner, Matias, additional, Xu, Manting, additional, Fang, Fang, additional, Ghezzi, Daniele, additional, Mayr, Johannes A., additional, Piekutowska-Abramczuk, Dorota, additional, Ribes, Antonia, additional, Rötig, Agnès, additional, Taylor, Robert W., additional, Wortmann, Saskia B., additional, Murayama, Kei, additional, Meitinger, Thomas, additional, Gagneur, Julien, additional, and Prokisch, Holger, additional

Published
2021
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31. Integration of proteomics with genomics and transcriptomics increases the diagnostic rate of Mendelian disorders

Author

Kopajtich, Robert, primary, Smirnov, Dmitrii, additional, Stenton, Sarah L., additional, Loipfinger, Stefan, additional, Meng, Chen, additional, Scheller, Ines F., additional, Freisinger, Peter, additional, Baski, Robert, additional, Berutti, Riccardo, additional, Behr, Jürgen, additional, Bucher, Martina, additional, Distelmaier, Felix, additional, Graf, Elisabeth, additional, Gusic, Mirjana, additional, Hempel, Maja, additional, Kulterer, Lea, additional, Mayr, Johannes, additional, Meitinger, Thomas, additional, Mertes, Christian, additional, Metodiev, Metodi D., additional, Nadel, Agnieszka, additional, Nasca, Alessia, additional, Ohtake, Akira, additional, Okazaki, Yasushi, additional, Olsen, Rikke, additional, Piekutowska-Abramczuk, Dorota, additional, Rötig, Agnès, additional, Santer, René, additional, Schindler, Detlev, additional, Slama, Abdelhamid, additional, Staufner, Christian, additional, Strom, Tim, additional, Verloo, Patrick, additional, von Kleist-Retzow, Jürgen-Christoph, additional, Wortmann, Saskia B., additional, Yépez, Vicente A., additional, Lamperti, Costanza, additional, Ghezzi, Daniele, additional, Murayama, Kei, additional, Ludwig, Christina, additional, Gagneur, Julien, additional, and Prokisch, Holger, additional

Published
2021
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33. Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance

Author

Stenton, Sarah L., primary, Piekutowska‐Abramczuk, Dorota, additional, Kulterer, Lea, additional, Kopajtich, Robert, additional, Claeys, Kristl G., additional, Ciara, Elżbieta, additional, Eisen, Johannes, additional, Płoski, Rafał, additional, Pronicka, Ewa, additional, Malczyk, Katarzyna, additional, Wagner, Matias, additional, Wortmann, Saskia B., additional, and Prokisch, Holger, additional

Published
2021
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39. phenotypic spectrum of COX20-associated mitochondrial disorder.

Author

Ban, Rui, Kopajtich, Robert, Lv, Junlan, Stenton, Sarah L, Shimura, Masaru, Wang, Zhaoxia, Yuan, Yun, Wang, Junling, Han, Xiaodi, Liu, Zhimei, Shi, Qiang, Pu, Chuanqiang, Prokisch, Holger, Fang, Fang, and Elstner, Matthias

Subjects
MITOCHONDRIAL pathology, DYSARTHRIA, GENE expression, PHENOTYPES
Abstract

Infantile onset hypotonia without neuropathy (n = 3 patients) This group includes the Turkish patient described in the original publication by Szklarczyk I et al i .,[2] as well as another Turkish[6] and an American[4] patient. In a recent article published in I Brain i , Dong and colleagues[1] reported on a new cohort of eight Chinese patients primarily affected by sensory neuropathy with an onset age of between 1 and 17 years. Later childhood-onset neuropathy/dystonia ataxia overlapping syndrome (n = 4 patients) Dystonia and cerebellar ataxia (DYTCA) syndrome is primarily associated with co-enzyme Q10 deficiency, but can be seen in I COX20 i patients in conjunction with neuropathy. [Extracted from the article]

Published
2022
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41. Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course

Author

Esposito, Alessandro, primary, Falace, Antonio, additional, Wagner, Matias, additional, Gal, Moran, additional, Mei, Davide, additional, Conti, Valerio, additional, Pisano, Tiziana, additional, Aprile, Davide, additional, Cerullo, Maria Sabina, additional, De Fusco, Antonio, additional, Giovedì, Silvia, additional, Seibt, Annette, additional, Magen, Daniella, additional, Polster, Tilman, additional, Eran, Ayelet, additional, Stenton, Sarah L, additional, Fiorillo, Chiara, additional, Ravid, Sarit, additional, Mayatepek, Ertan, additional, Hafner, Hava, additional, Wortmann, Saskia, additional, Levanon, Erez Y, additional, Marini, Carla, additional, Mandel, Hanna, additional, Benfenati, Fabio, additional, Distelmaier, Felix, additional, Fassio, Anna, additional, and Guerrini, Renzo, additional

Published
2019
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43. The diagnosis of inborn errors of metabolism by an integrative "multi‐omics" approach: A perspective encompassing genomics, transcriptomics, and proteomics.

Author

Stenton, Sarah L., Kremer, Laura S., Kopajtich, Robert, Ludwig, Christina, and Prokisch, Holger

Abstract

Given the rapidly decreasing cost and increasing speed and accessibility of massively parallel technologies, the integration of comprehensive genomic, transcriptomic, and proteomic data into a "multi‐omics" diagnostic pipeline is within reach. Even though genomic analysis has the capability to reveal all possible perturbations in our genetic code, analysis typically reaches a diagnosis in just 35% of cases, with a diagnostic gap arising due to limitations in prioritization and interpretation of detected variants. Here we review the utility of complementing genetic data with transcriptomic data and give a perspective for the introduction of proteomics into the diagnostic pipeline. Together these methodologies enable comprehensive capture of the functional consequence of variants, unobtainable by the analysis of each methodology in isolation. This facilitates functional annotation and reprioritization of candidate genes and variants—a promising approach to shed light on the underlying molecular cause of a patient's disease, increasing diagnostic rate, and allowing actionability in clinical practice. [ABSTRACT FROM AUTHOR]

Published
2020
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44. Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations

Author

Stenton, Sarah L., Pejaver, Vikas, Bergquist, Timothy, Biesecker, Leslie G., Byrne, Alicia B., Nadeau, Emily A.W., Greenblatt, Marc S., Harrison, Steven M., Tavtigian, Sean V., Radivojac, Predrag, Brenner, Steven E., O’Donnell-Luria, Anne, Biesecker, Leslie G., Harrison, Steven M., Tayoun, Ahmad A., Berg, Jonathan S., Brenner, Steven E., Cutting, Garry R., Ellard, Sian, Greenblatt, Marc S., Kang, Peter, Karbassi, Izabela, Karchin, Rachel, Mester, Jessica, O’Donnell-Luria, Anne, Pesaran, Tina, Plon, Sharon E., Rehm, Heidi L., Strande, Natasha T., Tavtigian, Sean V., and Topper, Scott

Abstract

: To investigate the number of rare missense variants observed in human genome sequences by ACMG/AMP PP3/BP4 evidence strength, following the calibrated PP3/BP4 computational recommendations.

Published
2024
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46. Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria.

Author

Bergquist T, Stenton SL, Nadeau EAW, Byrne AB, Greenblatt MS, Harrison SM, Tavtigian SV, O'Donnell-Luria A, Biesecker LG, Radivojac P, Brenner SE, and Pejaver V

Abstract

Purpose: We previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up to Strong . A new generation of tools using distinctive approaches have since been released, and these methods must be independently calibrated for clinical application., Method: Using our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by three new tools (AlphaMissense, ESM1b, VARITY) and calibrated scores meeting each evidence strength., Results: All three tools reached the Strong level of evidence for variant pathogenicity and Moderate for benignity, though sometimes for few variants. Compared to previously recommended tools, these yielded at best only modest improvements in the tradeoffs of evidence strength and false positive predictions., Conclusion: At calibrated thresholds, three new computational predictors provided evidence for variant pathogenicity at similar strength to the four previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field., Competing Interests: CONFLICT OF INTEREST L.G.B. is a member of the Illumina Medical Ethics Committee, receives research support from Merck, Inc., and royalties from Wolters-Kluwer. V.P. and P.R. participated in the development of some of the tools assessed in this study. A.O’D.L. receives research support from PacBio and is a consultant for Addition Therapeutics and on the SAB for Congenica Inc.

Published
2024
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47. Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.

Author

Negi S, Stenton SL, Berger SI, McNulty B, Violich I, Gardner J, Hillaker T, O'Rourke SM, O'Leary MC, Carbonell E, Austin-Tse C, Lemire G, Serrano J, Mangilog B, VanNoy G, Kolmogorov M, Vilain E, O'Donnell-Luria A, Délot E, Miga KH, Monlong J, and Paten B

Abstract

More than 50% of families with suspected rare monogenic diseases remain unsolved after whole genome analysis by short read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing, and providing haplotype-resolved methylation profiling. To evaluate LRS's additional diagnostic yield, we sequenced a rare disease cohort of 98 samples, including 41 probands and some family members, using nanopore sequencing, achieving per sample ∼36x average coverage and 32 kilobase (kb) read N50 from a single flow cell. Our Napu pipeline generated assemblies, phased variants, and methylation calls. LRS covered, on average, coding exons in ∼280 genes and ∼5 known Mendelian disease genes that were not covered by SRS. In comparison to SRS, LRS detected additional rare, functionally annotated variants, including SVs and tandem repeats, and completely phased 87% of protein-coding genes. LRS detected additional de novo variants, and could be used to distinguish postzygotic mosaic variants from prezygotic de novos . Eleven probands were solved, with diverse underlying genetic causes including de novo and compound heterozygous variants, large-scale SVs, and epigenetic modifications. Our study demonstrates LRS's potential to enhance diagnostic yield for rare monogenic diseases, implying utility in future clinical genomics workflows.

Published
2024
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48. Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.

Author

Gudmundsson S, Singer-Berk M, Stenton SL, Goodrich JK, Wilson MW, Einson J, Watts NA, Lappalainen T, Rehm HL, MacArthur DG, and O'Donnell-Luria A

Abstract

Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants (pLoF) in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. We identified explanations for the presumed lack of disease manifestation in 701 of the variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders rarely occur, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue., Competing Interests: COMPETING INTERESTS A.O-D.L. is on the scientific advisory board for Congenica, receives research funding in the form of reagents from Pacific Biosciences, and is a paid advisor to Addition Therapeutics and former advisor to Tome Biosciences and Ono Pharma USA. D.G.M. is a paid adviser to GlaxoSmithKline, Insitro, and Overtone Therapeutics, and receives research funding from Microsoft Corporation. H.L.R. receives research funding from Microsoft. T.L. is an advisor and has equity in Variant Bio.

Published
2024
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49. De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

Author

Chen Y, Dawes R, Kim HC, Stenton SL, Walker S, Ljungdahl A, Lord J, Ganesh VS, Ma J, Martin-Geary AC, Lemire G, D'Souza EN, Dong S, Ellingford JM, Adams DR, Allan K, Bakshi M, Baldwin EE, Berger SI, Bernstein JA, Brown NJ, Burrage LC, Chapman K, Compton AG, Cunningham CA, D'Souza P, Délot EC, Dias KR, Elias ER, Evans CA, Ewans L, Ezell K, Fraser JL, Gallacher L, Genetti CA, Grant CL, Haack T, Kuechler A, Lalani SR, Leitão E, Fevre AL, Leventer RJ, Liebelt JE, Lockhart PJ, Ma AS, Macnamara EF, Maurer TM, Mendez HR, Montgomery SB, Nassogne MC, Neumann S, O'Leary M, Palmer EE, Phillips J, Pitsava G, Pysar R, Rehm HL, Reuter CM, Revencu N, Riess A, Rius R, Rodan L, Roscioli T, Rosenfeld JA, Sachdev R, Simons C, Sisodiya SM, Snell P, Clair L, Stark Z, Tan TY, Tan NB, Temple SE, Thorburn DR, Tifft CJ, Uebergang E, VanNoy GE, Vilain E, Viskochil DH, Wedd L, Wheeler MT, White SM, Wojcik M, Wolfe LA, Wolfenson Z, Xiao C, Zocche D, Rubenstein JL, Markenscoff-Papadimitriou E, Fica SM, Baralle D, Depienne C, MacArthur DG, Howson JM, Sanders SJ, O'Donnell-Luria A, and Whiffin N

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals., Competing Interests: Competing interests NW receives research funding from Novo Nordisk and has consulted for ArgoBio studio. SJS receives research funding from BioMarin Pharmaceutical. AODL is on the scientific advisory board for Congenica, was a paid consultant for Tome Biosciences and Ono Pharma USA Inc., and received reagents from PacBio to support rare disease research. HLR has received support from Illumina and Microsoft to support rare disease gene discovery and diagnosis. MHW has consulted for Illumina and Sanofi and received speaking honoraria from Illumina and GeneDx. SBM is an advisor for BioMarin, Myome and Tenaya Therapeutics. SMS has received honoraria for educational events or advisory boards from Angelini Pharma, Biocodex, Eisai, Zogenix/UCB and institutional contributions for advisory boards, educational events or consultancy work from Eisai, Jazz/GW Pharma, Stoke Therapeutics, Takeda, UCB and Zogenix. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. JMMH is a full-time employee of Novo Nordisk and holds shares in Novo Nordisk A/S. DGM is a paid consultant for GlaxoSmithKline, Insitro, and Overtone Therapeutics and receives research support from Microsoft.

Published
2024
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50. Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations.

Author

Stenton SL, Pejaver V, Bergquist T, Biesecker LG, Byrne AB, Nadeau E, Greenblatt MS, Harrison S, Tavtigian S, Radivojac P, Brenner SE, and O'Donnell-Luria A

Abstract

Purpose: To investigate the number of rare missense variants observed in human genome sequences by ACMG/AMP PP3/BP4 evidence strength, following the calibrated PP3/BP4 computational recommendations., Methods: Missense variants from the genome sequences of 300 probands from the Rare Genomes Project with suspected rare disease were analyzed using computational prediction tools able to reach PP3_Strong and BP4_Moderate evidence strengths (BayesDel, MutPred2, REVEL, and VEST4). The numbers of variants at each evidence strength were analyzed across disease-associated genes and genome-wide., Results: From a median of 75.5 rare (≤1% allele frequency) missense variants in disease-associated genes per proband, a median of one reached PP3_Strong, 3-5 PP3_Moderate, and 3-5 PP3_Supporting. Most were allocated BP4 evidence (median 41-49 per proband) or were indeterminate (median 17.5-19 per proband). Extending the analysis to all protein-coding genes genome-wide, the number of PP3_Strong variants increased approximately 2.6-fold compared to disease-associated genes, with a median per proband of 1-3 PP3_Strong, 8-16 PP3_Moderate, and 10-17 PP3_Supporting., Conclusion: A small number of variants per proband reached PP3_Strong and PP3_Moderate in 3,424 disease-associated genes, and though not the intended use of the recommendations, also genome-wide. Use of PP3/BP4 evidence as recommended from calibrated computational prediction tools in the clinical diagnostic laboratory is unlikely to inappropriately contribute to the classification of an excessive number of variants as Pathogenic or Likely Pathogenic by ACMG/AMP rules., Competing Interests: CONFLICT OF INTEREST Disclosure: L.G.B. receives royalties from Wolters-Kluwer for authorship of UpToDate, is a member of the Illumina Medical Ethics Committee, and receives research support from Merck, Inc. V.P. and P.R. participated in the development of some of the tools assessed in this study. All other authors declare no conflict of interest.

Published
2024
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