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1. Pushing the boundaries of rare disease diagnostics with the help of the first Undiagnosed Hackathon

Author

Delgado-Vega, Angelica Maria, Cederroth, Helene, Taylan, Fulya, Ekholm, Katja, Ek, Marlene, Thonberg, Håkan, Jemt, Anders, Nilsson, Daniel, Eisfeldt, Jesper, Bilgrav Saether, Kristine, Höijer, Ida, Akgun-Dogan, Ozlem, Asano, Yui, Barakat, Tahsin Stefan, Batkovskyte, Dominyka, Baynam, Gareth, Bodamer, Olaf, Chetruengchai, Wanna, Corcoran, Pádraic, Couse, Madeline, Danis, Daniel, Demidov, German, Dohi, Eisuke, Erhardsson, Mattias, Fernandez-Luna, Luis, Fujiwara, Toyofumi, Garg, Neha, Giugliani, Roberto, Gonzaga-Jauregui, Claudia, Grigelioniene, Giedre, Groza, Tudor, Gunnarsson, Cecilia, Hammarsjö, Anna, Hammond, Charles Kumi, Hatirnaz Ng, Özden, Hesketh, Sirisha, Hettiarachchi, Dineshani, Johansson Soller, Maria, Kirmani, Umn Ahmed, Kjellberg, Martin, Kvarnung, Malin, Kvlividze, Oleg, Lagerstedt-Robinson, Kristina, Lasko, Paul, Lassmann, Timo, Lau, Lynette Y. S., Laurie, Steven, Lim, Weng Khong, Liu, Zhandong, Lysenkova Wiklander, Mariya, Makay, Prince, Maiga, Alassane Baneye, Maya-González, Carolina, Meyn, M. Stephen, Neethiraj, Ramprasad, Nigro, Vincenzo, Nordgren, Felix, Nordlund, Jessica, Orrsjö, Sara, Ottosson, Jesper, Ozbek, Ugur, Özdemir, Özkan, Partin, Clyde, Pearce, David A., Peck, Raquel, Pedersen, Annie, Pettersson, Maria, Pongpanich, Monnat, Posada de la Paz, Manuel, Ramani, Arun, Romero, Juan Andres, Romero, Vanessa I., Rosenquist, Richard, Saw, Aung Min, Spencer, Matthew, Stattin, Eva-Lena, Srichomthong, Chalurmpon, Tapia-Paez, Isabel, Taruscio, Domenica, Taylor, Julie P., Tkemaladze, Tinatin, Tully, Ian, Tümer, Zeynep, van Zelst-Stams, Wendy A. G., Verloes, Alain, Västerviga, Emma, Wang, Sailan, Yang, Rachel, Yamamoto, Shinya, Yépez, Vicente A., Zhang, Qing, Shotelersuk, Vorasuk, Wiafe, Samuel Agyei, Alanay, Yasemin, Botto, Lorenzo D., Kirmani, Salman, Lumaka, Aimé, Palmer, Elizabeth Emma, Puri, Ratna Dua, Wirta, Valtteri, Lindstrand, Anna, Buske, Orion J., Cederroth, Mikk, and Nordgren, Ann

Published
2024
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2. Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression

Author

Pehlivan, Davut, Bengtsson, Jesse D., Bajikar, Sameer S., Grochowski, Christopher M., Lun, Ming Yin, Gandhi, Mira, Jolly, Angad, Trostle, Alexander J., Harris, Holly K., Suter, Bernhard, Aras, Sukru, Ramocki, Melissa B., Du, Haowei, Mehaffey, Michele G., Park, KyungHee, Wilkey, Ellen, Karakas, Cemal, Eisfeldt, Jesper J., Pettersson, Maria, Liu, Lynn, Shinawi, Marwan S., Kimonis, Virginia E., Wiszniewski, Wojciech, Mckenzie, Kyle, Roser, Timo, Vianna-Morgante, Angela M., Cornier, Alberto S., Abdelmoity, Ahmed, Hwang, James P., Jhangiani, Shalini N., Muzny, Donna M., Mitani, Tadahiro, Muramatsu, Kazuhiro, Nabatame, Shin, Glaze, Daniel G., Fatih, Jawid M., Gibbs, Richard A., Liu, Zhandong, Lindstrand, Anna, Sedlazeck, Fritz J., Lupski, James R., Zoghbi, Huda Y., and Carvalho, Claudia M. B.

Published
2024
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5. Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci

Author

Grochowski, Christopher M., Bengtsson, Jesse D., Du, Haowei, Gandhi, Mira, Lun, Ming Yin, Mehaffey, Michele G., Park, KyungHee, Höps, Wolfram, Benito, Eva, Hasenfeld, Patrick, Korbel, Jan O., Mahmoud, Medhat, Paulin, Luis F., Jhangiani, Shalini N., Hwang, James Paul, Bhamidipati, Sravya V., Muzny, Donna M., Fatih, Jawid M., Gibbs, Richard A., Pendleton, Matthew, Harrington, Eoghan, Juul, Sissel, Lindstrand, Anna, Sedlazeck, Fritz J., Pehlivan, Davut, Lupski, James R., and Carvalho, Claudia M.B.

Published
2024
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9. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Author

Gillentine, Madelyn A, Wang, Tianyun, Hoekzema, Kendra, Rosenfeld, Jill, Liu, Pengfei, Guo, Hui, Kim, Chang N, De Vries, Bert BA, Vissers, Lisenka ELM, Nordenskjold, Magnus, Kvarnung, Malin, Lindstrand, Anna, Nordgren, Ann, Gecz, Jozef, Iascone, Maria, Cereda, Anna, Scatigno, Agnese, Maitz, Silvia, Zanni, Ginevra, Bertini, Enrico, Zweier, Christiane, Schuhmann, Sarah, Wiesener, Antje, Pepper, Micah, Panjwani, Heena, Torti, Erin, Abid, Farida, Anselm, Irina, Srivastava, Siddharth, Atwal, Paldeep, Bacino, Carlos A, Bhat, Gifty, Cobian, Katherine, Bird, Lynne M, Friedman, Jennifer, Wright, Meredith S, Callewaert, Bert, Petit, Florence, Mathieu, Sophie, Afenjar, Alexandra, Christensen, Celenie K, White, Kerry M, Elpeleg, Orly, Berger, Itai, Espineli, Edward J, Fagerberg, Christina, Brasch-Andersen, Charlotte, Hansen, Lars Kjærsgaard, Feyma, Timothy, Hughes, Susan, Thiffault, Isabelle, Sullivan, Bonnie, Yan, Shuang, Keller, Kory, Keren, Boris, Mignot, Cyril, Kooy, Frank, Meuwissen, Marije, Basinger, Alice, Kukolich, Mary, Philips, Meredith, Ortega, Lucia, Drummond-Borg, Margaret, Lauridsen, Mathilde, Sorensen, Kristina, Lehman, Anna, CAUSES Study, Lopez-Rangel, Elena, Levy, Paul, Lessel, Davor, Lotze, Timothy, Madan-Khetarpal, Suneeta, Sebastian, Jessica, Vento, Jodie, Vats, Divya, Benman, L Manace, Mckee, Shane, Mirzaa, Ghayda M, Muss, Candace, Pappas, John, Peeters, Hilde, Romano, Corrado, Elia, Maurizio, Galesi, Ornella, Simon, Marleen EH, van Gassen, Koen LI, Simpson, Kara, Stratton, Robert, Syed, Sabeen, Thevenon, Julien, Palafoll, Irene Valenzuela, Vitobello, Antonio, Bournez, Marie, Faivre, Laurence, Xia, Kun, SPARK Consortium, Earl, Rachel K, Nowakowski, Tomasz, Bernier, Raphael A, and Eichler, Evan E

Subjects
CAUSES Study, SPARK Consortium, Cortex development, Gene families, Neurodevelopmental disorders, hnRNPs, Genetics, Clinical Sciences
Abstract

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Published
2021

10. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Commerce, Management, Tourism and Services, SPARK Consortium
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

11. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Basic Helix-Loop-Helix Transcription Factors, CCCTC-Binding Factor, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein U, High-Throughput Nucleotide Sequencing, Humans, KCNQ3 Potassium Channel, Male, Mutation, Neurodevelopmental Disorders, RNA-Binding Proteins, Repressor Proteins, Transcription Factors, SPARK Consortium
Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF

Published
2020

12. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Author

Cogné, Benjamin, Ehresmann, Sophie, Beauregard-Lacroix, Eliane, Rousseau, Justine, Besnard, Thomas, Garcia, Thomas, Petrovski, Slavé, Avni, Shiri, McWalter, Kirsty, Blackburn, Patrick R, Sanders, Stephan J, Uguen, Kévin, Harris, Jacqueline, Cohen, Julie S, Blyth, Moira, Lehman, Anna, Berg, Jonathan, Li, Mindy H, Kini, Usha, Joss, Shelagh, von der Lippe, Charlotte, Gordon, Christopher T, Humberson, Jennifer B, Robak, Laurie, Scott, Daryl A, Sutton, Vernon R, Skraban, Cara M, Johnston, Jennifer J, Poduri, Annapurna, Nordenskjöld, Magnus, Shashi, Vandana, Gerkes, Erica H, Bongers, Ernie MHF, Gilissen, Christian, Zarate, Yuri A, Kvarnung, Malin, Lally, Kevin P, Kulch, Peggy A, Daniels, Brina, Hernandez-Garcia, Andres, Stong, Nicholas, McGaughran, Julie, Retterer, Kyle, Tveten, Kristian, Sullivan, Jennifer, Geisheker, Madeleine R, Stray-Pedersen, Asbjorg, Tarpinian, Jennifer M, Klee, Eric W, Sapp, Julie C, Zyskind, Jacob, Holla, Øystein L, Bedoukian, Emma, Filippini, Francesca, Guimier, Anne, Picard, Arnaud, Busk, Øyvind L, Punetha, Jaya, Pfundt, Rolph, Lindstrand, Anna, Nordgren, Ann, Kalb, Fayth, Desai, Megha, Ebanks, Ashley Harmon, Jhangiani, Shalini N, Dewan, Tammie, Coban Akdemir, Zeynep H, Telegrafi, Aida, Zackai, Elaine H, Begtrup, Amber, Song, Xiaofei, Toutain, Annick, Wentzensen, Ingrid M, Odent, Sylvie, Bonneau, Dominique, Latypova, Xénia, Deb, Wallid, CAUSES Study, Redon, Sylvia, Bilan, Frédéric, Legendre, Marine, Troyer, Caitlin, Whitlock, Kerri, Caluseriu, Oana, Murphree, Marine I, Pichurin, Pavel N, Agre, Katherine, Gavrilova, Ralitza, Rinne, Tuula, Park, Meredith, Shain, Catherine, Heinzen, Erin L, Xiao, Rui, Amiel, Jeanne, Lyonnet, Stanislas, Isidor, Bertrand, Biesecker, Leslie G, Lowenstein, Dan, Posey, Jennifer E, and Denommé-Pichon, Anne-Sophie

Subjects
CAUSES Study, Deciphering Developmental Disorders study, Humans, Syndrome, Adaptor Proteins, Signal Transducing, Nuclear Proteins, Prognosis, Autistic Disorder, Amino Acid Sequence, Sequence Homology, Mutation, Missense, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Young Adult, Genetic Association Studies, Intellectual Disability, TRRAP, autism spectrum disorder, congenital malformations, de novo variants, histone acetylation, intellectual disability, neurodevelopmental disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, Genetics, Brain Disorders, Neurosciences, Mental Health, Autism, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Mental health, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Published
2019

13. Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability

Author

Lindstrand, Anna, Ek, Marlene, Kvarnung, Malin, Anderlid, Britt-Marie, Björck, Erik, Carlsten, Jonas, Eisfeldt, Jesper, Grigelioniene, Giedre, Gustavsson, Peter, Hammarsjö, Anna, Helgadóttir, Hafdís T., Hellström-Pigg, Maritta, Kuchinskaya, Ekaterina, Lagerstedt-Robinson, Kristina, Levin, Lars-Åke, Lieden, Agne, Lindelöf, Hillevi, Malmgren, Helena, Nilsson, Daniel, Svensson, Eva, Paucar, Martin, Sahlin, Ellika, Tesi, Bianca, Tham, Emma, Winberg, Johanna, Winerdal, Max, Wincent, Josephine, Johansson Soller, Maria, Pettersson, Maria, and Nordgren, Ann

Published
2022
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15. Implementing precision medicine in a regionally organized healthcare system in Sweden

Author

Fioretos, Thoas, Wirta, Valtteri, Cavelier, Lucia, Berglund, Eva, Friedman, Mikaela, Akhras, Michael, Botling, Johan, Ehrencrona, Hans, Engstrand, Lars, Helenius, Gisela, Fagerqvist, Therese, Gisselsson, David, Gruvberger-Saal, Sofia, Gyllensten, Ulf, Heidenblad, Markus, Höglund, Kina, Jacobsson, Bo, Johansson, Maria, Johansson, Åsa, Soller, Maria Johansson, Landström, Maréne, Larsson, Pär, Levin, Lars-Åke, Lindstrand, Anna, Lovmar, Lovisa, Lyander, Anna, Melin, Malin, Nordgren, Ann, Nordmark, Gunnel, Mölling, Paula, Palmqvist, Lars, Palmqvist, Richard, Repsilber, Dirk, Sikora, Per, Stenmark, Bianca, Söderkvist, Peter, Stranneheim, Henrik, Strid, Tobias, Wheelock, Craig E., Wadelius, Mia, Wedell, Anna, Edsjö, Anders, and Rosenquist, Richard

Published
2022
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17. Trailblazing precision medicine in Europe: A joint view by Genomic Medicine Sweden and the Centers for Personalized Medicine, ZPM, in Germany

Author

Lindstrand, Anna, Wedell, Anna, Gisselsson, David, Melén, Erik, Helenius, Gisela, Ehrencrona, Hans, Engstrand, Lars, Palmqvist, Lars, Levin, Lars-Åke, Lovmar, Lovisa, Landström, Maréne, Hallbeck, Martin, Wadelius, Mia, Sikora, Per, Beer, Ambros J., Illert, Anna L., Budczies, Jan, Nikolaou, Konstantin, Kohlbacher, Oliver, Horak, Peter, Kuhn, Peter, Schroeder, Christopher, Boerries, Melanie, Lassmann, Silke, Gaidzik, Verena I., Stenzinger, Albrecht, Edsjö, Anders, Ploeger, Carolin, Friedman, Mikaela, Fröhling, Stefan, Wirta, Valtteri, Seufferlein, Thomas, Botling, Johan, Duyster, Justus, Akhras, Michael, Thimme, Robert, Fioretos, Thoas, Bitzer, Michael, Cavelier, Lucia, Schirmacher, Peter, Malek, Nisar, and Rosenquist, Richard

Published
2022
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18. Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant

Author

Boer, Elke de, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Gao, Fei, Gilissen, Christian, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Matalonga, Leslie, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, Paske, Iris B.A.W. te, Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, Trimouille, Aurélien, van der Velde, Joeri K., Vandrovcova, Jana, Vitobello, Antonio, Zurek, Birte, Abbot, Kristin M., Banka, Siddharth, Benetti, Elisa, de Boer, Elke, Casari, Giorgio, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Ellwanger, Kornelia, Faivre, Laurence, Graessner, Holm, Haack, Tobias B., Hammarsjö, Anna, Havlovicova, Marketa, Hoischen, Alexander, Hugon, Anne, Jackson, Adam, Kerstjens, Mieke, Kleefstra, Tjitske, Lindstrand, Anna, Martín, Estrella López, Macek, Milan, Jr., Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca C., Renieri, Alessandra, Rooryck, Caroline, Ryba, Lukas, Santen, Gijs W.E., Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Verloes, Alain, Vissers, Lisenka, Votypka, Pavel, Vyshka, Klea, Zguro, Kristina, Yaldiz, Burcu, Laurie, Steve, de Reuver, Rick, Kwint, Michael, Pfundt, Rolph, Willemsen, Michèl A.A.P., Vries, Bert B.A. de, Vitobello, A., and Vissers, Lisenka E.L.M.

Published
2022
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20. High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses

Author

Hammarsjö, Anna, Pettersson, Maria, Chitayat, David, Handa, Atsuhiko, Anderlid, Britt-Marie, Bartocci, Marco, Basel, Donald, Batkovskyte, Dominyka, Beleza-Meireles, Ana, Conner, Peter, Eisfeldt, Jesper, Girisha, Katta M., Chung, Brian Hon-Yin, Horemuzova, Eva, Hyodo, Hironobu, Korņejeva, Liene, Lagerstedt-Robinson, Kristina, Lin, Angela E., Magnusson, Måns, Moosa, Shahida, Nayak, Shalini S., Nilsson, Daniel, Ohashi, Hirofumi, Ohashi-Fukuda, Naoko, Stranneheim, Henrik, Taylan, Fulya, Traberg, Rasa, Voss, Ulrika, Wirta, Valtteri, Nordgren, Ann, Nishimura, Gen, Lindstrand, Anna, and Grigelioniene, Giedre

Published
2021
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21. DLG4-related synaptopathy: a new rare brain disorder

Author

Rodríguez-Palmero, Agustí, Boerrigter, Melissa Maria, Gómez-Andrés, David, Aldinger, Kimberly A., Marcos-Alcalde, Íñigo, Popp, Bernt, Everman, David B., Lovgren, Alysia Kern, Arpin, Stephanie, Bahrambeigi, Vahid, Beunders, Gea, Bisgaard, Anne-Marie, Bjerregaard, V.A., Bruel, Ange-Line, Challman, Thomas D., Cogné, Benjamin, Coubes, Christine, de Man, Stella A., Denommé-Pichon, Anne-Sophie, Dye, Thomas J., Elmslie, Frances, Feuk, Lars, García-Miñaúr, Sixto, Gertler, Tracy, Giorgio, Elisa, Gruchy, Nicolas, Haack, Tobias B., Haldeman-Englert, Chad R., Haukanes, Bjørn Ivar, Hoyer, Juliane, Hurst, Anna C.E., Isidor, Bertrand, Soller, Maria Johansson, Kushary, Sulagna, Kvarnung, Malin, Landau, Yuval E., Leppig, Kathleen A., Lindstrand, Anna, Kleinendorst, Lotte, MacKenzie, Alex, Mandrile, Giorgia, Mendelsohn, Bryce A., Moghadasi, Setareh, Morton, Jenny E., Moutton, Sebastien, Müller, Amelie J., O’Leary, Melanie, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Pfundt, Rolph, Pode-Shakked, Ben, Rauch, Anita, Repnikova, Elena, Revah-Politi, Anya, Ross, Meredith J., Ruivenkamp, Claudia A.L., Sarrazin, Elisabeth, Savatt, Juliann M., Schlüter, Agatha, Schönewolf-Greulich, Bitten, Shad, Zohra, Shaw-Smith, Charles, Shieh, Joseph T., Shohat, Motti, Spranger, Stephanie, Thiese, Heidi, Mau-Them, Frederic Tran, van Bon, Bregje, van de Burgt, Ineke, van de Laar, Ingrid M.B.H., van Drie, Esmée, van Haelst, Mieke M., van Ravenswaaij-Arts, Conny M., Verdura, Edgard, Vitobello, Antonio, Waldmüller, Stephan, Whiting, Sharon, Zweier, Christiane, Prada, Carlos E., de Vries, Bert B.A., Dobyns, William B., Reiter, Simone F., Gómez-Puertas, Paulino, Pujol, Aurora, and Tümer, Zeynep

Published
2021
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22. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Author

Stessman, Holly AF, Xiong, Bo, Coe, Bradley P, Wang, Tianyun, Hoekzema, Kendra, Fenckova, Michaela, Kvarnung, Malin, Gerdts, Jennifer, Trinh, Sandy, Cosemans, Nele, Vives, Laura, Lin, Janice, Turner, Tychele N, Santen, Gijs, Ruivenkamp, Claudia, Kriek, Marjolein, van Haeringen, Arie, Aten, Emmelien, Friend, Kathryn, Liebelt, Jan, Barnett, Christopher, Haan, Eric, Shaw, Marie, Gecz, Jozef, Anderlid, Britt-Marie, Nordgren, Ann, Lindstrand, Anna, Schwartz, Charles, Kooy, R Frank, Vandeweyer, Geert, Helsmoortel, Celine, Romano, Corrado, Alberti, Antonino, Vinci, Mirella, Avola, Emanuela, Giusto, Stefania, Courchesne, Eric, Pramparo, Tiziano, Pierce, Karen, Nalabolu, Srinivasa, Amaral, David G, Scheffer, Ingrid E, Delatycki, Martin B, Lockhart, Paul J, Hormozdiari, Fereydoun, Harich, Benjamin, Castells-Nobau, Anna, Xia, Kun, Peeters, Hilde, Nordenskjöld, Magnus, Schenck, Annette, Bernier, Raphael A, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Behavioral and Social Science, Genetic Testing, Intellectual and Developmental Disabilities (IDD), Mental Health, Neurosciences, Pediatric, Autism, Aetiology, 2.1 Biological and endogenous factors, Mental health, Autistic Disorder, Developmental Disabilities, Female, Humans, Intellectual Disability, Male, Mutation, Phenotype, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Published
2017

24. Genome sequencing differentiates a paracentric inversion from a balanced insertion enabling more accurate preimplantation genetic testing.

Author

Wincent, Josephine, Helgadóttir, Hafdís T., Sergouniotis, Fotios, Salazar Mantero, Angelo, Carvalho, Claudia M. B., Malmgren, Helena, Lindstrand, Anna, and Iwarsson, Erik

Subjects
NUCLEOTIDE sequencing, GENETIC testing, RECURRENT miscarriage, FLUORESCENCE in situ hybridization, CHROMOSOME inversions, Y chromosome
Abstract

Introduction: Distinguishing paracentric inversions (PAIs) from chromosomal insertions has traditionally relied on fluorescent in situ hybridization (FISH) techniques, but recent advancements in high‐throughput sequencing have enabled the use of genome sequencing for such differentiation. In this study, we present a 38‐year‐old male carrier of a paracentric inversion on chromosome 2q, inv (2)(q31.2q34), whose partner experienced recurrent miscarriages. Material and Methods: FISH analysis confirmed the inversion, and genome sequencing was employed for detailed characterization. Results: Preimplantation genetic testing (PGT) revealed that all assessed embryos were balanced, consistent with the low risk of unbalanced offspring associated with PAIs. While PAI carriers traditionally exhibit low risk of producing unbalanced offspring, exceptions exist due to crossover events within the inversion loop. Although the sample size was limited, the findings align with existing sperm study data, supporting the rare occurrence of unbalanced progeny in PAI carriers. Conclusions: This study highlights the possibility of characterizing PAIs using genome sequencing to enable correct reproductive counseling and PGT decisions. Detailed characterization of a PAI is crucial for understanding potential outcomes and guiding PGT strategies, as accurate knowledge of the inversion size is essential for appropriate method selection in PGT. Given the very low risk of unbalanced offspring in PAI carriers, routine PGT may not be warranted but should be considered in specific cases with a history of unbalanced progeny or recurrent miscarriages. This study contributes to our understanding of PAI segregation and its implications for reproductive outcomes. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients

Author

Stranneheim, Henrik, Lagerstedt-Robinson, Kristina, Magnusson, Måns, Kvarnung, Malin, Nilsson, Daniel, Lesko, Nicole, Engvall, Martin, Anderlid, Britt-Marie, Arnell, Henrik, Johansson, Carolina Backman, Barbaro, Michela, Björck, Erik, Bruhn, Helene, Eisfeldt, Jesper, Freyer, Christoph, Grigelioniene, Giedre, Gustavsson, Peter, Hammarsjö, Anna, Hellström-Pigg, Maritta, Iwarsson, Erik, Jemt, Anders, Laaksonen, Mikael, Enoksson, Sara Lind, Malmgren, Helena, Naess, Karin, Nordenskjöld, Magnus, Oscarson, Mikael, Pettersson, Maria, Rasi, Chiara, Rosenbaum, Adam, Sahlin, Ellika, Sardh, Eliane, Stödberg, Tommy, Tesi, Bianca, Tham, Emma, Thonberg, Håkan, Töhönen, Virpi, von Döbeln, Ulrika, Vassiliou, Daphne, Vonlanthen, Sofie, Wikström, Ann-Charlotte, Wincent, Josephine, Winqvist, Ola, Wredenberg, Anna, Ygberg, Sofia, Zetterström, Rolf H., Marits, Per, Soller, Maria Johansson, Nordgren, Ann, Wirta, Valtteri, Lindstrand, Anna, and Wedell, Anna

Published
2021
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27. Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Author

Bakshi, Madhura, Wilson, Meredith, Berman, Yemina, Dickson, Rebecca, Fransen, Erik, Helsmoortel, Céline, Van den Ende, Jenneke, Van der Aa, Nathalie, van de Wijdeven, Marina J., Rosenblum, Jessica, Monteiro, Fabíola, Kok, Fernando, Quercia, Nada, Bowdin, Sarah, Dyment, David, Chitayat, David, Alkhunaizi, Ebba, Boonen, Susanne E., Keren, Boris, Jacquette, Aurelia, Faivre, Laurence, Bezieau, Stephane, Isidor, Bertrand, Rieß, Angelika, Moog, Ute, Lynch, Sally Ann, McVeigh, Terri, Elpeleg, Orly, Smeland, Marie Falkenberg, Fannemel, Madeleine, van Haeringen, Arie, Maas, Saskia M., Veenstra-Knol, H.E., Schouten, Meyke, Willemsen, Marjolein H., Marcelis, Carlo L., Ockeloen, Charlotte, van der Burgt, Ineke, Feenstra, Ilse, van der Smagt, Jasper, Jezela-Stanek, Aleksandra, Krajewska-Walasek, Malgorzata, González-Lamuño, Domingo, Anderlid, Britt-Marie, Malmgren, Helena, Nordenskjöld, Magnus, Clement, Emma, Hurst, Jane, Metcalfe, Kay, Mansour, Sahar, Lachlan, Katherine, Clayton-Smith, Jill, Hendon, Laura G., Abdulrahman, Omar A., Morrow, Eric, McMillan, Clare, Gerdts, Jennifer, Peeden, Joseph, Schrier Vergano, Samantha A., Valentino, Caitlin, Chung, Wendy K., Ozmore, Jillian R., Bedrosian-Sermone, Sandra, Dennis, Anna, Treat, Kayla, Hughes, Susan Starling, Safina, Nicole, Le Pichon, Jean-Baptiste, McGuire, Marianne, Infante, Elena, Madan-Khetarpal, Suneeta, Desai, Sonal, Benke, Paul, Krokosky, Alyson, Cristian, Ingrid, Baker, Laura, Gripp, Karen, Stessman, Holly A., Eichenberger, Jacob, Jayakar, Parul, Pizzino, Amy, Manning, Melanie Ann, Slattery, Leah, Van Dijck, Anke, Vulto-van Silfhout, Anneke T., Cappuyns, Elisa, van der Werf, Ilse M., Mancini, Grazia M., Tzschach, Andreas, Bernier, Raphael, Gozes, Illana, Eichler, Evan E., Romano, Corrado, Lindstrand, Anna, Nordgren, Ann, Kvarnung, Malin, Kleefstra, Tjitske, de Vries, Bert B.A., Küry, Sébastien, Rosenfeld, Jill A., Meuwissen, Marije E., Vandeweyer, Geert, and Kooy, R. Frank

Published
2019
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28. Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures

Author

Grochowski, Christopher M., primary, Bengtsson, Jesse D., additional, Du, Haowei, additional, Gandhi, Mira, additional, Lun, Ming Yin, additional, Mehaffey, Michele G., additional, Park, KyungHee, additional, Höps, Wolfram, additional, Benito-Garagorri, Eva, additional, Hasenfeld, Patrick, additional, Korbel, Jan O., additional, Mahmoud, Medhat, additional, Paulin, Luis F., additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Fatih, Jawid M., additional, Gibbs, Richard A., additional, Pendleton, Matthew, additional, Harrington, Eoghan, additional, Juul, Sissel, additional, Lindstrand, Anna, additional, Sedlazeck, Fritz J., additional, Pehlivan, Davut, additional, Lupski, James R., additional, and Carvalho, Claudia M.B., additional

Published
2023
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33. Reduced cone photoreceptor function and subtle systemic manifestations in two siblings with loss of SCLT1.

Author

Grudzinska Pechhacker, Monika K, Molnar, Anna, Pekkola Pacheco, Nadja, Thonberg, Håkan, Querat, Laurence, Birkeldh, Ulrika, Nordgren, Ann, and Lindstrand, Anna

Subjects
PHOTORECEPTORS, DYSTROPHY, FUNDUS oculi, ATTENTION-deficit hyperactivity disorder, GENETIC testing, LAURENCE-Moon-Biedl syndrome, GENETIC variation, KIDNEY physiology
Abstract

The sodium channel and clathrin linker 1 gene (SCLT1) has been involved in the pathogenesis of various ciliopathy disorders such as Bardet-Biedl syndrome, orofaciodigital syndrome type IX, and Senior-Løken syndrome. Detailed exams are warranted to outline all clinical features. Here, we present a family with a milder phenotype of SCLT1-related disease. Comprehensive eye examination including fundus images, OCT, color vision, visual fields and electroretinography were performed. Affected individuals were assessed by a pediatrician and a medical geneticist for systemic features of ciliopathy. Investigations included echocardiography, abdominal ultrasonography, blood work-up for diabetes, liver and kidney function. Genetic testing included NGS retinal dystrophy panel, segregation analysis and transcriptome sequencing. Two male children, age 10 and 8 years, were affected with attention deficit hyperactivity disorder (ADHD), obesity and mild photophobia. The ophthalmic exam revealed reduced best-corrected visual acuity (BCVA), strabismus, hyperopia, astigmatism and moderate red-green defects. Milder changes suggesting photoreceptors disease were found on retinal imaging. Electroretinogram confirmed cone photoreceptors dysfunction. Genetic testing revealed a homozygous likely pathogenic, splice-site variant in SCLT1 gene NM_144643.3: c.1439 + 1del in the proband and in the affected brother. The unaffected parents were heterozygous for the SCLT1 variant. Transcriptome sequencing showed retention of intron 16 in the proband. In this report, we highlight the importance of further extensive diagnostics in patients with unexplained reduced vision, strabismus, refractive errors and ADHD spectrum disorders. SCLT1-related retinal degeneration is very rare and isolated reduced function of cone photoreceptors has not previously been observed. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Case report: Extending the spectrum of clinical and molecular findings in FOXC1 haploinsufficiency syndrome

Author

Garza Flores, Alexandra, primary, Nordgren, Ida, additional, Pettersson, Maria, additional, Dias-Santagata, Dora, additional, Nilsson, Daniel, additional, Hammarsjö, Anna, additional, Lindstrand, Anna, additional, Batkovskyte, Dominyka, additional, Wiggs, Janey, additional, Walton, David S., additional, Goldenberg, Paula, additional, Eisfeldt, Jesper, additional, Lin, Angela E., additional, Lachman, Ralph S., additional, Nishimura, Gen, additional, and Grigelioniene, Giedre, additional

Published
2023
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36. Precision medicine in rare diseases: What is next?

Author

Tesi, Bianca, primary, Boileau, Catherine, additional, Boycott, Kym M., additional, Canaud, Guillaume, additional, Caulfield, Mark, additional, Choukair, Daniela, additional, Hill, Sue, additional, Spielmann, Malte, additional, Wedell, Anna, additional, Wirta, Valtteri, additional, Nordgren, Ann, additional, and Lindstrand, Anna, additional

Published
2023
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37. Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders

Author

Ek, Marlene, primary, Nilsson, Daniel, additional, Engvall, Martin, additional, Malmgren, Helena, additional, Thonberg, Håkan, additional, Pettersson, Maria, additional, Anderlid, Britt-Marie, additional, Hammarsjö, Anna, additional, Helgadottir, Hafdis T., additional, Arnardottir, Snjolaug, additional, Naess, Karin, additional, Nennesmo, Inger, additional, Paucar, Martin, additional, Hjartarson, Helgi Thor, additional, Press, Rayomand, additional, Solders, Göran, additional, Sejersen, Thomas, additional, Lindstrand, Anna, additional, and Kvarnung, Malin, additional

Published
2023
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38. A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies

Author

Aranda‐Guillén, Maribel, primary, Røyrvik, Ellen Christine, additional, Fletcher‐Sandersjöö, Sara, additional, Artaza, Haydee, additional, Botusan, Ileana Ruxandra, additional, Grytaas, Marianne A., additional, Hallgren, Åsa, additional, Breivik, Lars, additional, Pettersson, Maria, additional, Jørgensen, Anders P., additional, Lindstrand, Anna, additional, Vogt, Elinor, additional, Husebye, Eystein S., additional, Kämpe, Olle, additional, Wolff, Anette S. Bøe, additional, Bensing, Sophie, additional, Johansson, Stefan, additional, and Eriksson, Daniel, additional

Published
2023
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40. Precision medicine in rare diseases : What is next?

Author

Tesi, Bianca, Boileau, Catherine, Boycott, Kym M., Canaud, Guillaume, Caulfield, Mark, Choukair, Daniela, Hill, Sue, Spielmann, Malte, Wedell, Anna, Wirta, Valtteri, Nordgren, Ann, Lindstrand, Anna, Tesi, Bianca, Boileau, Catherine, Boycott, Kym M., Canaud, Guillaume, Caulfield, Mark, Choukair, Daniela, Hill, Sue, Spielmann, Malte, Wedell, Anna, Wirta, Valtteri, Nordgren, Ann, and Lindstrand, Anna

Abstract

Molecular diagnostics is a cornerstone of modern precision medicine, broadly understood as tailoring an individual's treatment, follow-up, and care based on molecular data. In rare diseases (RDs), molecular diagnoses reveal valuable information about the cause of symptoms, disease progression, familial risk, and in certain cases, unlock access to targeted therapies. Due to decreasing DNA sequencing costs, genome sequencing (GS) is emerging as the primary method for precision diagnostics in RDs. Several ongoing European initiatives for precision medicine have chosen GS as their method of choice. Recent research supports the role for GS as first-line genetic investigation in individuals with suspected RD, due to its improved diagnostic yield compared to other methods. Moreover, GS can detect a broad range of genetic aberrations including those in noncoding regions, producing comprehensive data that can be periodically reanalyzed for years to come when further evidence emerges. Indeed, targeted drug development and repurposing of medicines can be accelerated as more individuals with RDs receive a molecular diagnosis. Multidisciplinary teams in which clinical specialists collaborate with geneticists, genomics education of professionals and the public, and dialogue with patient advocacy groups are essential elements for the integration of precision medicine into clinical practice worldwide. It is also paramount that large research projects share genetic data and leverage novel technologies to fully diagnose individuals with RDs. In conclusion, GS increases diagnostic yields and is a crucial step toward precision medicine for RDs. Its clinical implementation will enable better patient management, unlock targeted therapies, and guide the development of innovative treatments., QC 20231023

Published
2023
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41. Building a precision medicine infrastructure at a national level: The Swedish experience

Author

Edsjö, Anders, Lindstrand, Anna, Gisselsson, David, Mölling, Paula, Friedman, Mikaela, Cavelier, Lucia, Johansson, Maria, Ehrencrona, Hans, Fagerqvist, Therese, Strid, Tobias, Lovmar, Lovisa, Jacobsson, Bo, Johansson, Åsa, Engstrand, Lars, Wheelock, Craig E, Sikora, Per, Wirta, Valtteri, Fioretos, Thoas, Rosenquist, Richard, Edsjö, Anders, Lindstrand, Anna, Gisselsson, David, Mölling, Paula, Friedman, Mikaela, Cavelier, Lucia, Johansson, Maria, Ehrencrona, Hans, Fagerqvist, Therese, Strid, Tobias, Lovmar, Lovisa, Jacobsson, Bo, Johansson, Åsa, Engstrand, Lars, Wheelock, Craig E, Sikora, Per, Wirta, Valtteri, Fioretos, Thoas, and Rosenquist, Richard

Abstract

Precision medicine has the potential to transform healthcare by moving from one-size-fits-all to personalised treatment and care. This transition has been greatly facilitated through new high-throughput sequencing technologies that can provide the unique molecular profile of each individual patient, along with the rapid development of targeted therapies directed to the Achilles heels of each disease. To implement precision medicine approaches in healthcare, many countries have adopted national strategies and initiated genomic/precision medicine initiatives to provide equal access to all citizens. In other countries, such as Sweden, this has proven more difficult due to regionally organised healthcare. Using a bottom-up approach, key stakeholders from academia, healthcare, industry and patient organisations joined forces and formed Genomic Medicine Sweden (GMS), a national infrastructure for the implementation of precision medicine across the country. To achieve this, Genomic Medicine Centres have been established to provide regionally distributed genomic services, and a national informatics infrastructure has been built to allow secure data handling and sharing. GMS has a broad scope focusing on rare diseases, cancer, pharmacogenomics, infectious diseases and complex diseases, while also providing expertise in informatics, ethical and legal issues, health economy, industry collaboration and education. In this review, we summarise our experience in building a national infrastructure for precision medicine. We also provide key examples how precision medicine already has been successfully implemented within our focus areas. Finally, we bring up challenges and opportunities associated with precision medicine implementation, the importance of international collaboration, as well as the future perspective in the field of precision medicine., Funding agencies: GMS is supported by the strategic innovation program Swelife and Vinnova, the Swedish Innovation Agency; the Ministry of Health and Social Affairs; SciLifeLab; the Swedish Childhood Cancer Fund; funding from the participating healthcare regions Region Skåne, Region Västra Götaland, Region Östergötland, Region Stockholm, Region Uppsala, Region Västerbotten and Region Örebro län and the medical faculties at Gothenburg University, Linköping University, Lund University, Karolinska Institutet, Umeå University, Uppsala University and Örebro University. SciLifeLab provides funding to the Clinical Genomics platform and to several projects performed in collaboration with GMS as a partner. Illumina has provided reagents for sequencing a subset of the patients in the acute leukaemia combined WGS and WTS study.

Published
2023
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42. Transposable element insertions in 1000 Swedish individuals

Author

Saether, Kristine Bilgrav, Nilsson, Daniel, Thonberg, Håkan, Tham, Emma, Ameur, Adam, Eisfeldt, Jesper, Lindstrand, Anna, Saether, Kristine Bilgrav, Nilsson, Daniel, Thonberg, Håkan, Tham, Emma, Ameur, Adam, Eisfeldt, Jesper, and Lindstrand, Anna

Abstract

The majority of rare diseases are genetic, and regardless of advanced high-throughput genomics-based investigations, 60% of patients remain undiagnosed. A major factor limiting our ability to identify disease-causing alterations is a poor understanding of the morbid and normal human genome. A major genomic contributor of which function and distribution remain largely unstudied are the transposable elements (TE), which constitute 50% of our genome. Here we aim to resolve this knowledge gap and increase the diagnostic yield of rare disease patients investigated with clinical genome sequencing. To this end we characterized TE insertions in 1000 Swedish individuals from the SweGen dataset and 2504 individuals from the 1000 Genomes Project (1KGP), creating seven population-specific TE insertion databases. Of note, 66% of TE insertions in SweGen were present at > 1% in the 1KGP databases, proving that most insertions are common across populations. Focusing on the rare TE insertions, we show that even though similar to 0.7% of those insertions affect protein coding genes, they rarely affect known disease casing genes (< 0.1%). Finally, we applied a TE insertion identification workflow on two clinical cases where disease causing TE insertions were suspected and could verify the presence of pathogenic TE insertions in both. Altogether we demonstrate the importance of TE insertion detection and highlight possible clinical implications in rare disease diagnostics.

Published
2023
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43. A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies

Author

Aranda-Guillén, Maribel, Røyrvik, Ellen Christine, Fletcher-Sandersjöö, Sara, Artaza, Haydee, Botusan, Ileana Ruxandra, Grytaas, Marianne A., Hallgren, Åsa, Breivik, Lars, Pettersson, Maria, Jørgensen, Anders P., Lindstrand, Anna, Vogt, Elinor, Husebye, Eystein S., Kämpe, Olle, Bøe Wolff, Anette S., Bensing, Sophie, Johansson, Stefan, Eriksson, Daniel, Aranda-Guillén, Maribel, Røyrvik, Ellen Christine, Fletcher-Sandersjöö, Sara, Artaza, Haydee, Botusan, Ileana Ruxandra, Grytaas, Marianne A., Hallgren, Åsa, Breivik, Lars, Pettersson, Maria, Jørgensen, Anders P., Lindstrand, Anna, Vogt, Elinor, Husebye, Eystein S., Kämpe, Olle, Bøe Wolff, Anette S., Bensing, Sophie, Johansson, Stefan, and Eriksson, Daniel

Abstract

Background: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients. Methods: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI. Results: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies. Conclusions: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.

Published
2023
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44. Loss of ctnnd2b affects neuronal differentiation and behavior in zebrafish

Author

Vaz, Raquel, Edwards, Steven, Duenas-Rey, Alfredo, Hofmeister, Wolfgang, Lindstrand, Anna, Vaz, Raquel, Edwards, Steven, Duenas-Rey, Alfredo, Hofmeister, Wolfgang, and Lindstrand, Anna

Abstract

Delta-catenin (CTNND2) is an adhesive junction associated protein belonging to the family of p120 catenins. The human gene is located on the short arm of chromosome 5, the region deleted in Cri-du-chat syndrome (OMIM #123450). Heterozygous loss of CTNND2 has been linked to a wide spectrum of neurodevelopmental disorders such as autism, schizophrenia, and intellectual disability. Here we studied how heterozygous loss of ctnnd2b affects zebrafish embryonic development, and larvae and adult behavior. First, we observed a disorganization of neuronal subtypes in the developing forebrain, namely the presence of ectopic isl1-expressing cells and a local reduction of GABA-positive neurons in the optic recess region. Next, using time-lapse analysis, we found that the disorganized distribution of is1l-expressing forebrain neurons resulted from an increased specification of Isl1:GFP neurons. Finally, we studied the swimming patterns of both larval and adult heterozygous zebrafish and observed an increased activity compared to wildtype animals. Overall, this data suggests a role for ctnnd2b in the differentiation cascade of neuronal subtypes in specific regions of the vertebrate brain, with repercussions in the animal's behavior., QC 20230803

Published
2023
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45. Precision medicine and rare diseases in pediatric urology

Author

Nordgren, Ann, Lindstrand, Anna, Wu, Hsi-Yang, Fossum, Magdalena, Nordgren, Ann, Lindstrand, Anna, Wu, Hsi-Yang, and Fossum, Magdalena

Abstract

Precision Medicine holds promise for helping us manage specific phenotypes of common diseases. For rare diseases such as hypospadias, DSD, and pediatric solid tumors, it can also reveal underlying risk factors and pathogenesis. Professors Ann Nordgren and Anna Lindstrand share their experiences in the development and ongoing initiatives of the Swedish national project on Precision Medicine and how it could change the care of pediatric urology patients.

Published
2023

46. Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement

Author

Aleck, Kirk, Banki, Zoltan, Dudas, Joszef, Dumfahrt, Herbert, Haririan, Hady, Hartsfield, James K., Kagen, Charles N., Lindert, Uschi, Meitinger, Thomas, Posch, Wilfried, Pritz, Christian, Ross, David, Schroer, Richard J., Wick, Georg, Wildin, Robert, Wilflingseder, Doris, Kapferer-Seebacher, Ines, Pepin, Melanie, Werner, Roland, Aitman, Timothy J., Nordgren, Ann, Stoiber, Heribert, Thielens, Nicole, Gaboriaud, Christine, Amberger, Albert, Schossig, Anna, Gruber, Robert, Giunta, Cecilia, Bamshad, Michael, Björck, Erik, Chen, Christina, Chitayat, David, Dorschner, Michael, Schmitt-Egenolf, Marcus, Hale, Christopher J., Hanna, David, Hennies, Hans Christian, Heiss-Kisielewsky, Irene, Lindstrand, Anna, Lundberg, Pernilla, Mitchell, Anna L., Nickerson, Deborah A., Reinstein, Eyal, Rohrbach, Marianne, Romani, Nikolaus, Schmuth, Matthias, Silver, Rachel, Taylan, Fulya, Vandersteen, Anthony, Vandrovcova, Jana, Weerakkody, Ruwan, Yang, Margaret, Pope, F. Michael, Byers, Peter H., and Zschocke, Johannes

Published
2016
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49. From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability

Author

Lindstrand, Anna, Eisfeldt, Jesper, Pettersson, Maria, Carvalho, Claudia M. B., Kvarnung, Malin, Grigelioniene, Giedre, Anderlid, Britt-Marie, Bjerin, Olof, Gustavsson, Peter, Hammarsjö, Anna, Georgii-Hemming, Patrik, Iwarsson, Erik, Johansson-Soller, Maria, Lagerstedt-Robinson, Kristina, Lieden, Agne, Magnusson, Måns, Martin, Marcel, Malmgren, Helena, Nordenskjöld, Magnus, Norling, Ameli, Sahlin, Ellika, Stranneheim, Henrik, Tham, Emma, Wincent, Josephine, Ygberg, Sofia, Wedell, Anna, Wirta, Valtteri, Nordgren, Ann, Lundin, Johanna, and Nilsson, Daniel

Published
2019
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