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1. Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

Author

Guo, Long, Salian, Smrithi, Xue, Jing-Yi, Rath, Nicola, Rousseau, Justine, Kim, Hyunyun, Ehresmann, Sophie, Moosa, Shahida, Nakagawa, Norio, Kuroda, Hiroshi, Clayton-Smith, Jill, Wang, Juan, Wang, Zheng, Banka, Siddharth, Jackson, Adam, Zhang, Yan-Min, Wei, Zhen-Jie, Hüning, Irina, Brunet, Theresa, Ohashi, Hirofumi, Thomas, Molly, Bupp, Caleb, Miyake, Noriko, Matsumoto, Naomichi, Mendoza-Londono, Roberto, Costain, Gregory, Hahn, Gabriele, Di Donato, Nataliya, Yigit, Gökhan, Yamada, Takahiro, Nishimura, Gen, Ansel, Karl, Wollnik, Bernd, Hrabě de Angelis, Martin, Mégarbané, André, Rosenfeld, Jill, Heissmeyer, Vigo, Ikegawa, Shiro, and Campeau, Philippe

Subjects
ERI1, exoribonuclease, ribosomopathy, short stature, skeletal dysplasia, spondyloepimetaphyseal dysplasia, Humans, Exoribonucleases, Histones, Mutation, Missense, RNA, Ribosomal, 5.8S, RNA, RNA, Messenger
Abstract

ERI1 is a 3-to-5 exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3 end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Published
2023

2. Bi-allelic variants in INTS11 are associated with a complex neurological disorder

Author

Acosta, Maria T., Adam, Margaret, Adams, David R., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Deardorff, Matthew, Dell'Angelica, Esteban C., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Falk, Marni, Fernandez, Liliana, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Godfrey, Rena A., Golden-Grant, Katie, Goldrich, Madison P., Grajewski, Alana, Gutierrez, Irma, Hadley, Don, Hahn, Sihoun, Hamid, Rizwan, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Karaviti, Lefkothea, Kennedy, Jennifer, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Lalani, Seema R., Lam, Byron, Lam, Christina, LaMoure, Grace L., Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Mahoney, Rachel, Mak, Bryan C., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Nakano-Okuno, Mariko, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Potocki, Lorraine, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Raper, Anna, Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, C. Ron, Scott, Daryl A., Shashi, Vandana, Shin, Jimann, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Krezel, Lilianna Solnica, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Jennifer A., Sullivan, Kathleen, Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Amelia L.M., Tan, Queenie K.- G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Wallace, Stephanie, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Weisz-Hubshman, Monika, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Worley, Kim, Xiao, Changrui, Yamamoto, Shinya, Yang, John, Zastrow, Diane B., Zhang, Zhe, Zhao, Chunli, Zuchner, Stephan, Tepe, Burak, Macke, Erica L., Niceta, Marcello, Weisz Hubshman, Monika, Kanca, Oguz, Schultz-Rogers, Laura, Zarate, Yuri A., Schaefer, G. Bradley, Granadillo De Luque, Jorge Luis, Wegner, Daniel J., Cogne, Benjamin, Gilbert-Dussardier, Brigitte, Le Guillou, Xavier, Wagner, Eric J., Pais, Lynn S., Neil, Jennifer E., Mochida, Ganeshwaran H., Walsh, Christopher A., Magal, Nurit, Drasinover, Valerie, Shohat, Mordechai, Schwab, Tanya, Schmitz, Chris, Clark, Karl, Fine, Anthony, Lanpher, Brendan, Gavrilova, Ralitza, Blanc, Pierre, Burglen, Lydie, Afenjar, Alexandra, Steel, Dora, Kurian, Manju A., Prabhakar, Prab, Gößwein, Sophie, Di Donato, Nataliya, Bertini, Enrico S., Tartaglia, Marco, and Klee, Eric W.

Published
2023
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3. Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay

Author

Lee, Sangmoon, Chen, Dillon Y, Zaki, Maha S, Maroofian, Reza, Houlden, Henry, Di Donato, Nataliya, Abdin, Dalia, Morsy, Heba, Mirzaa, Ghayda M, Dobyns, William B, McEvoy-Venneri, Jennifer, Stanley, Valentina, James, Kiely N, Mancini, Grazia MS, Schot, Rachel, Kalayci, Tugba, Altunoglu, Umut, Karimiani, Ehsan Ghayoor, Brick, Lauren, Kozenko, Mariya, Jamshidi, Yalda, Manzini, M Chiara, Toosi, Mehran Beiraghi, and Gleeson, Joseph G

Subjects
Biological Sciences, Neurosciences, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Neurological, Alleles, Classical Lissencephalies and Subcortical Band Heterotopias, Cytoskeletal Proteins, Developmental Disabilities, Female, Humans, Lissencephaly, Male, Pedigree, APC2, agyria, band heterotopia, epilepsy, intellectual disability, lissencephaly, neuronal migration, pachygyria, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

Published
2019

6. Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay

Author

Melo, Uirá Souto, Bonner, Devon, Kent Lloyd, Kevin C., Moshiri, Ala, Willis, Brandon, Lanoue, Louise, Bower, Lynette, Leonard, Brian C., Martins, Davi Jardim, Gomes, Fernando, de Souza Leite, Felipe, Oliveira, Danyllo, Kitajima, João Paulo, Monteiro, Fabiola P., Zatz, Mayana, Menck, Carlos Frederico Martins, Wheeler, Matthew T., Bernstein, Jonathan A., Dumas, Kevin, Spiteri, Elizabeth, Di Donato, Nataliya, Jahn, Arne, Hashem, Mais, Alsaif, Hessa S., Chedrawi, Aziza, Alkuraya, Fowzan S., Kok, Fernando, and Byers, Heather M.

Published
2021
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8. The clinical-phenotype continuum in DYNC1H1-related disorders—genomic profiling and proposal for a novel classification

Author

Becker, Lena-Luise, Dafsari, Hormos Salimi, Schallner, Jens, Abdin, Dalia, Seifert, Michael, Petit, Florence, Smol, Thomas, Bok, Levinus, Rodan, Lance, Krapels, Ingrid, Spranger, Stephanie, Weschke, Bernhard, Johnson, Katherine, Straub, Volker, Kaindl, Angela M., Di Donato, Nataliya, von der Hagen, Maja, and Cirak, Sebahattin

Published
2020
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9. International consensus recommendations on the diagnostic work-up for malformations of cortical development

Author

Oegema, Renske, Barakat, Tahsin Stefan, Wilke, Martina, Stouffs, Katrien, Amrom, Dina, Aronica, Eleonora, Bahi-Buisson, Nadia, Conti, Valerio, Fry, Andrew E., Geis, Tobias, Andres, David Gomez, Parrini, Elena, Pogledic, Ivana, Said, Edith, Soler, Doriette, Valor, Luis M., Zaki, Maha S., Mirzaa, Ghayda, Dobyns, William B., Reiner, Orly, Guerrini, Renzo, Pilz, Daniela T., Hehr, Ute, Leventer, Richard J., Jansen, Anna C., Mancini, Grazia M. S., and Di Donato, Nataliya

Published
2020
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10. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Blok, Lot Snijders, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot RF, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T, Hoischen, Alexander, Vissers, Lisenka ELM, Koemans, Tom S, Wissink-Lindhout, Willemijn, Eichler, Evan E, Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, van Bon, Bregje WM, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L, Van Dijck, Anke, Innes, A Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J, Henderson, Alex, Lynch, Sally A, Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Study, the DDD, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, van Gassen, Koen LI, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L, Pediaditakis, Igor, Haas, Stefan A, Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G, Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C, Stein, Quinn, Strauss, Kevin A, Brigatti, Karlla W, Keating, Katherine, Burton, Barbara K, Kim, Katherine H, Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D, Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M, van Roozendaal, Kees, Brunner, Han, Chung, Wendy K, Kooy, R Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G, Katsanis, Nicholas, and Kleefstra, Tjitske

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Intellectual and Developmental Disabilities (IDD), Human Genome, Clinical Research, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Amino Acid Substitution, Animals, Base Sequence, DEAD-box RNA Helicases, Embryo, Nonmammalian, Exome, Female, Gene Dosage, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Sequence Analysis, DNA, Sex Characteristics, Wnt Signaling Pathway, Zebrafish, DDD Study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Published
2015

12. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Author

Kaiser, Frank J, Ansari, Morad, Braunholz, Diana, Concepción Gil-Rodríguez, María, Decroos, Christophe, Wilde, Jonathan J, Fincher, Christopher T, Kaur, Maninder, Bando, Masashige, Amor, David J, Atwal, Paldeep S, Bahlo, Melanie, Bowman, Christine M, Bradley, Jacquelyn J, Brunner, Han G, Clark, Dinah, Del Campo, Miguel, Di Donato, Nataliya, Diakumis, Peter, Dubbs, Holly, Dyment, David A, Eckhold, Juliane, Ernst, Sarah, Ferreira, Jose C, Francey, Lauren J, Gehlken, Ulrike, Guillén-Navarro, Encarna, Gyftodimou, Yolanda, Hall, Bryan D, Hennekam, Raoul, Hudgins, Louanne, Hullings, Melanie, Hunter, Jennifer M, Yntema, Helger, Innes, A Micheil, Kline, Antonie D, Krumina, Zita, Lee, Hane, Leppig, Kathleen, Lynch, Sally Ann, Mallozzi, Mark B, Mannini, Linda, McKee, Shane, Mehta, Sarju G, Micule, Ieva, Care4Rare Canada Consortium, Mohammed, Shehla, Moran, Ellen, Mortier, Geert R, Moser, Joe-Ann S, Noon, Sarah E, Nozaki, Naohito, Nunes, Luis, Pappas, John G, Penney, Lynette S, Pérez-Aytés, Antonio, Petersen, Michael B, Puisac, Beatriz, Revencu, Nicole, Roeder, Elizabeth, Saitta, Sulagna, Scheuerle, Angela E, Schindeler, Karen L, Siu, Victoria M, Stark, Zornitza, Strom, Samuel P, Thiese, Heidi, Vater, Inga, Willems, Patrick, Williamson, Kathleen, Wilson, Louise C, University of Washington Center for Mendelian Genomics, Hakonarson, Hakon, Quintero-Rivera, Fabiola, Wierzba, Jolanta, Musio, Antonio, Gillessen-Kaesbach, Gabriele, Ramos, Feliciano J, Jackson, Laird G, Shirahige, Katsuhiko, Pié, Juan, Christianson, David W, Krantz, Ian D, Fitzpatrick, David R, and Deardorff, Matthew A

Subjects
Care4Rare Canada Consortium, University of Washington Center for Mendelian Genomics, Humans, Hypertelorism, De Lange Syndrome, Eye Abnormalities, Histone Deacetylases, Repressor Proteins, Cohort Studies, Sequence Alignment, Amino Acid Sequence, Phenotype, Mutation, Missense, Molecular Sequence Data, Child, Child, Preschool, Infant, Female, Male, Genes, X-Linked, Cranial Fontanelles, Genetics, Rare Diseases, Dental/Oral and Craniofacial Disease, Intellectual and Developmental Disabilities (IDD), Pediatric, Brain Disorders, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Aetiology, Congenital, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Published
2014

13. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly

Author

Di Donato, Nataliya, Timms, Andrew E, Aldinger, Kimberly A, Mirzaa, Ghayda M, Bennett, James T, Collins, Sarah, Olds, Carissa, Mei, Davide, Chiari, Sara, Carvill, Gemma, Myers, Candace T, Rivière, Jean-Baptiste, Zaki, Maha S, University of Washington Center for Mendelian Genomics, Gleeson, Joseph G, Rump, Andreas, Conti, Valerio, Parrini, Elena, Ross, M Elizabeth, Ledbetter, David H, Guerrini, Renzo, and Dobyns, William B

Published
2018
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15. Bi-allelic variants in INTS11 are associated with a complex neurological disorder

Author

Tepe, Burak, primary, Macke, Erica L., additional, Niceta, Marcello, additional, Weisz Hubshman, Monika, additional, Kanca, Oguz, additional, Schultz-Rogers, Laura, additional, Zarate, Yuri A., additional, Schaefer, G. Bradley, additional, Granadillo De Luque, Jorge Luis, additional, Wegner, Daniel J., additional, Cogne, Benjamin, additional, Gilbert-Dussardier, Brigitte, additional, Le Guillou, Xavier, additional, Wagner, Eric J., additional, Pais, Lynn S., additional, Neil, Jennifer E., additional, Mochida, Ganeshwaran H., additional, Walsh, Christopher A., additional, Magal, Nurit, additional, Drasinover, Valerie, additional, Shohat, Mordechai, additional, Schwab, Tanya, additional, Schmitz, Chris, additional, Clark, Karl, additional, Fine, Anthony, additional, Lanpher, Brendan, additional, Gavrilova, Ralitza, additional, Blanc, Pierre, additional, Burglen, Lydie, additional, Afenjar, Alexandra, additional, Steel, Dora, additional, Kurian, Manju A., additional, Prabhakar, Prab, additional, Gößwein, Sophie, additional, Di Donato, Nataliya, additional, Bertini, Enrico S., additional, Wangler, Michael F., additional, Yamamoto, Shinya, additional, Tartaglia, Marco, additional, Klee, Eric W., additional, Bellen, Hugo J., additional, Acosta, Maria T., additional, Adam, Margaret, additional, Adams, David R., additional, Alvey, Justin, additional, Amendola, Laura, additional, Andrews, Ashley, additional, Ashley, Euan A., additional, Azamian, Mahshid S., additional, Bacino, Carlos A., additional, Bademci, Guney, additional, Balasubramanyam, Ashok, additional, Baldridge, Dustin, additional, Bale, Jim, additional, Bamshad, Michael, additional, Barbouth, Deborah, additional, Bayrak-Toydemir, Pinar, additional, Beck, Anita, additional, Beggs, Alan H., additional, Behrens, Edward, additional, Bejerano, Gill, additional, Bennet, Jimmy, additional, Berg-Rood, Beverly, additional, Bernstein, Jonathan A., additional, Berry, Gerard T., additional, Bican, Anna, additional, Bivona, Stephanie, additional, Blue, Elizabeth, additional, Bohnsack, John, additional, Bonner, Devon, additional, Botto, Lorenzo, additional, Boyd, Brenna, additional, Briere, Lauren C., additional, Brokamp, Elly, additional, Brown, Gabrielle, additional, Burke, Elizabeth A., additional, Burrage, Lindsay C., additional, Butte, Manish J., additional, Byers, Peter, additional, Byrd, William E., additional, Carey, John, additional, Carrasquillo, Olveen, additional, Cassini, Thomas, additional, Peter Chang, Ta Chen, additional, Chanprasert, Sirisak, additional, Chao, Hsiao-Tuan, additional, Clark, Gary D., additional, Coakley, Terra R., additional, Cobban, Laurel A., additional, Cogan, Joy D., additional, Coggins, Matthew, additional, Cole, F. Sessions, additional, Colley, Heather A., additional, Cooper, Cynthia M., additional, Cope, Heidi, additional, Craigen, William J., additional, Crouse, Andrew B., additional, Cunningham, Michael, additional, D'Souza, Precilla, additional, Dai, Hongzheng, additional, Dasari, Surendra, additional, Davis, Joie, additional, Dayal, Jyoti G., additional, Deardorff, Matthew, additional, Dell'Angelica, Esteban C., additional, Dipple, Katrina, additional, Doherty, Daniel, additional, Dorrani, Naghmeh, additional, Doss, Argenia L., additional, Douine, Emilie D., additional, Duncan, Laura, additional, Earl, Dawn, additional, Eckstein, David J., additional, Emrick, Lisa T., additional, Eng, Christine M., additional, Esteves, Cecilia, additional, Falk, Marni, additional, Fernandez, Liliana, additional, Fieg, Elizabeth L., additional, Fisher, Paul G., additional, Fogel, Brent L., additional, Forghani, Irman, additional, Gahl, William A., additional, Glass, Ian, additional, Gochuico, Bernadette, additional, Godfrey, Rena A., additional, Golden-Grant, Katie, additional, Goldrich, Madison P., additional, Grajewski, Alana, additional, Gutierrez, Irma, additional, Hadley, Don, additional, Hahn, Sihoun, additional, Hamid, Rizwan, additional, Hassey, Kelly, additional, Hayes, Nichole, additional, High, Frances, additional, Hing, Anne, additional, Hisama, Fuki M., additional, Holm, Ingrid A., additional, Hom, Jason, additional, Horike-Pyne, Martha, additional, Huang, Alden, additional, Huang, Yong, additional, Introne, Wendy, additional, Isasi, Rosario, additional, Izumi, Kosuke, additional, Jamal, Fariha, additional, Jarvik, Gail P., additional, Jarvik, Jeffrey, additional, Jayadev, Suman, additional, Jean-Marie, Orpa, additional, Jobanputra, Vaidehi, additional, Karaviti, Lefkothea, additional, Kennedy, Jennifer, additional, Ketkar, Shamika, additional, Kiley, Dana, additional, Kilich, Gonench, additional, Kobren, Shilpa N., additional, Kohane, Isaac S., additional, Kohler, Jennefer N., additional, Krakow, Deborah, additional, Krasnewich, Donna M., additional, Kravets, Elijah, additional, Korrick, Susan, additional, Koziura, Mary, additional, Lalani, Seema R., additional, Lam, Byron, additional, Lam, Christina, additional, LaMoure, Grace L., additional, Lanpher, Brendan C., additional, Lanza, Ian R., additional, LeBlanc, Kimberly, additional, Lee, Brendan H., additional, Levitt, Roy, additional, Lewis, Richard A., additional, Liu, Pengfei, additional, Liu, Xue Zhong, additional, Longo, Nicola, additional, Loo, Sandra K., additional, Loscalzo, Joseph, additional, Maas, Richard L., additional, Macnamara, Ellen F., additional, MacRae, Calum A., additional, Maduro, Valerie V., additional, Mahoney, Rachel, additional, Mak, Bryan C., additional, Malicdan, May Christine V., additional, Mamounas, Laura A., additional, Manolio, Teri A., additional, Mao, Rong, additional, Maravilla, Kenneth, additional, Marom, Ronit, additional, Marth, Gabor, additional, Martin, Beth A., additional, Martin, Martin G., additional, Martínez-Agosto, Julian A., additional, Marwaha, Shruti, additional, McCauley, Jacob, additional, McConkie-Rosell, Allyn, additional, McCray, Alexa T., additional, McGee, Elisabeth, additional, Mefford, Heather, additional, Merritt, J. Lawrence, additional, Might, Matthew, additional, Mirzaa, Ghayda, additional, Morava, Eva, additional, Moretti, Paolo M., additional, Nakano-Okuno, Mariko, additional, Nelson, Stan F., additional, Newman, John H., additional, Nicholas, Sarah K., additional, Nickerson, Deborah, additional, Nieves-Rodriguez, Shirley, additional, Novacic, Donna, additional, Oglesbee, Devin, additional, Orengo, James P., additional, Pace, Laura, additional, Pak, Stephen, additional, Pallais, J. Carl, additional, Palmer, Christina GS., additional, Papp, Jeanette C., additional, Parker, Neil H., additional, Phillips, John A., additional, Posey, Jennifer E., additional, Potocki, Lorraine, additional, Pusey, Barbara N., additional, Quinlan, Aaron, additional, Raskind, Wendy, additional, Raja, Archana N., additional, Rao, Deepak A., additional, Raper, Anna, additional, Renteria, Genecee, additional, Reuter, Chloe M., additional, Rives, Lynette, additional, Robertson, Amy K., additional, Rodan, Lance H., additional, Rosenfeld, Jill A., additional, Rosenwasser, Natalie, additional, Rossignol, Francis, additional, Ruzhnikov, Maura, additional, Sacco, Ralph, additional, Sampson, Jacinda B., additional, Saporta, Mario, additional, Schaechter, Judy, additional, Schedl, Timothy, additional, Schoch, Kelly, additional, Scott, C. Ron, additional, Scott, Daryl A., additional, Shashi, Vandana, additional, Shin, Jimann, additional, Silverman, Edwin K., additional, Sinsheimer, Janet S., additional, Sisco, Kathy, additional, Smith, Edward C., additional, Smith, Kevin S., additional, Solem, Emily, additional, Krezel, Lilianna Solnica-, additional, Solomon, Ben, additional, Spillmann, Rebecca C., additional, Stoler, Joan M., additional, Sullivan, Jennifer A., additional, Sullivan, Kathleen, additional, Sun, Angela, additional, Sutton, Shirley, additional, Sweetser, David A., additional, Sybert, Virginia, additional, Tabor, Holly K., additional, Tan, Amelia L.M., additional, Tan, Queenie K.- G., additional, Tekin, Mustafa, additional, Telischi, Fred, additional, Thorson, Willa, additional, Tifft, Cynthia J., additional, Toro, Camilo, additional, Tran, Alyssa A., additional, Tucker, Brianna M., additional, Urv, Tiina K., additional, Vanderver, Adeline, additional, Velinder, Matt, additional, Viskochil, Dave, additional, Vogel, Tiphanie P., additional, Wahl, Colleen E., additional, Walker, Melissa, additional, Wallace, Stephanie, additional, Walley, Nicole M., additional, Wambach, Jennifer, additional, Wan, Jijun, additional, Wang, Lee-kai, additional, Ward, Patricia A., additional, Wegner, Daniel, additional, Weisz-Hubshman, Monika, additional, Wener, Mark, additional, Wenger, Tara, additional, Perry, Katherine Wesseling, additional, Westerfield, Monte, additional, Wheeler, Matthew T., additional, Whitlock, Jordan, additional, Wolfe, Lynne A., additional, Worley, Kim, additional, Xiao, Changrui, additional, Yang, John, additional, Zastrow, Diane B., additional, Zhang, Zhe, additional, Zhao, Chunli, additional, and Zuchner, Stephan, additional

Published
2023
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18. Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia

Author

Latham, Sharissa L., Ehmke, Nadja, Reinke, Patrick Y. A., Taft, Manuel H., Eicke, Dorothee, Reindl, Theresia, Stenzel, Werner, Lyons, Michael J., Friez, Michael J., Lee, Jennifer A., Hecker, Ramona, Frühwald, Michael C., Becker, Kerstin, Neuhann, Teresa M., Horn, Denise, Schrock, Evelin, Niehaus, Indra, Sarnow, Katharina, Grützmann, Konrad, Gawehn, Luzie, Klink, Barbara, Rump, Andreas, Chaponnier, Christine, Figueiredo, Constanca, Knöfler, Ralf, Manstein, Dietmar J., and Di Donato, Nataliya

Published
2018
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19. Author Correction: Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia

Author

Latham, Sharissa L., Ehmke, Nadja, Reinke, Patrick Y. A., Taft, Manuel H., Eicke, Dorothee, Reindl, Theresia, Stenzel, Werner, Lyons, Michael J., Friez, Michael J., Lee, Jennifer A., Hecker, Ramona, Frühwald, Michael C., Becker, Kerstin, Neuhann, Teresa M., Horn, Denise, Schrock, Evelin, Niehaus, Indra, Sarnow, Katharina, Grützmann, Konrad, Gawehn, Luzie, Klink, Barbara, Rump, Andreas, Chaponnier, Christine, Figueiredo, Constanca, Knöfler, Ralf, Manstein, Dietmar J., and Di Donato, Nataliya

Published
2018
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21. Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome

Author

Maas, Saskia M., Shaw, Adam C., Bikker, Hennie, Lüdecke, Hermann-Josef, van der Tuin, Karin, Badura-Stronka, Magdalena, Belligni, Elga, Biamino, Elisa, Bonati, Maria Teresa, Carvalho, Daniel R., Cobben, JanMaarten, de Man, Stella A., Den Hollander, Nicolette S., Di Donato, Nataliya, Garavelli, Livia, Grønborg, Sabine, Herkert, Johanna C., Hoogeboom, A. Jeannette M., Jamsheer, Aleksander, Latos-Bielenska, Anna, Maat-Kievit, Anneke, Magnani, Cinzia, Marcelis, Carlo, Mathijssen, Inge B., Nielsen, Maartje, Otten, Ellen, Ousager, Lilian B., Pilch, Jacek, Plomp, Astrid, Poke, Gemma, Poluha, Anna, Posmyk, Renata, Rieubland, Claudine, Silengo, Margharita, Simon, Marleen, Steichen, Elisabeth, Stumpel, Connie, Szakszon, Katalin, Polonkai, Edit, van den Ende, Jenneke, van der Steen, Antony, van Essen, Ton, van Haeringen, Arie, van Hagen, Johanna M., Verheij, Joke B.G.M., Mannens, Marcel M., and Hennekam, Raoul C.

Published
2015
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22. Clinical and functional characterization of germline PIK3CA variants in patients with PIK3CA-related overgrowth spectrum disorders

Author

Cooley Coleman, Jessica A, primary, Gass, Jennifer M, additional, Srikanth, Sujata, additional, Pauly, Rini, additional, Ziats, Catherine A, additional, Everman, David B, additional, Skinner, Steven A, additional, Bell, Shannon, additional, Louie, Raymond J, additional, Cascio, Lauren, additional, Patterson, Wesley G, additional, Jones, Julie R, additional, Di Donato, Nataliya, additional, Stevenson, Roger E, additional, and Boccuto, Luigi, additional

Published
2022
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23. The constitutional gain‐of‐function variant p. Glu1099Lys in NSD2 is associated with a novel syndrome

Author

Popp, Bernt, primary, Brugger, Melanie, additional, Poschmann, Sibylle, additional, Bartolomaeus, Tobias, additional, Radtke, Maximilian, additional, Hentschel, Julia, additional, Di Donato, Nataliya, additional, Rump, Andreas, additional, Gburek‐Augustat, Janina, additional, Graf, Elisabeth, additional, Wagner, Matias, additional, Sorge, Ina, additional, Lemke, Johannes R, additional, Meitinger, Thomas, additional, Abou Jamra, Rami, additional, Strehlow, Vincent, additional, and Brunet, Theresa, additional

Published
2022
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24. Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders

Author

Di Donato, Nataliya, primary, Guerrini, Renzo, additional, Billington, Charles J, additional, Barkovich, A James, additional, Dinkel, Philine, additional, Freri, Elena, additional, Heide, Michael, additional, Gershon, Elliot S, additional, Gertler, Tracy S, additional, Hopkin, Robert J, additional, Jacob, Suma, additional, Keedy, Sarah K, additional, Kooshavar, Daniz, additional, Lockhart, Paul J, additional, Lohmann, Dietmar R, additional, Mahmoud, Iman G, additional, Parrini, Elena, additional, Schrock, Evelin, additional, Severi, Giulia, additional, Timms, Andrew E, additional, Webster, Richard I, additional, Willis, Mary J H, additional, Zaki, Maha S, additional, Gleeson, Joseph G, additional, Leventer, Richard J, additional, and Dobyns, William B, additional

Published
2022
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25. The constitutional gain‐of‐function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome.

Author

Popp, Bernt, Brugger, Melanie, Poschmann, Sibylle, Bartolomaeus, Tobias, Radtke, Maximilian, Hentschel, Julia, Di Donato, Nataliya, Rump, Andreas, Gburek‐Augustat, Janina, Graf, Elisabeth, Wagner, Matias, Sorge, Ina, Lemke, Johannes R, Meitinger, Thomas, Abou Jamra, Rami, Strehlow, Vincent, and Brunet, Theresa

Subjects
GENE expression, MISSENSE mutation, DNA methylation, SYNDROMES, INTELLECTUAL disabilities, BETAINE
Abstract

NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf‐Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss‐of‐function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occurs somatically in leukemia and has a gain‐of‐function (GoF) effect. We describe two individuals carrying p.Glu1099Lys as heterozygous de novo germline variant identified by exome sequencing (ES) of blood DNA and subsequently confirmed in two ectodermal tissues. Clinically, these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly. Public cell lines with NSD2 GoF variants had increased K36me2, DNA promoter methylation, and dysregulated RNA expression. NSD2 GoF caused by p.Glu1099Lys is associated with a novel phenotype different from WHS and Rauch–Steindl syndrome (RAUST). [ABSTRACT FROM AUTHOR]

Published
2023
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28. Generation of iPSC lines from CPVT patient carrying heterozygous mutation p.A2254V in the ryanodine receptor 2 gene

Author

Li, Wener, Henze, Sarah, Luo, Xiaojing, Ulbricht, Ying, Richter, Anja, di Donato, Nataliya, Wilde, Arthur A. M., Guan, Kaomei, Cardiology, and ACS - Heart failure & arrhythmias

Subjects
QH301-705.5, Induced Pluripotent Stem Cells, Mutation, Tachycardia, Ventricular, cardiovascular system, Humans, Ryanodine Receptor Calcium Release Channel, Biology (General)
Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inheritable cardiac disorder, which is characterized by life-threatening cardiac arrhythmias, syncope, seizures, or sudden cardiac death in response to physical exercise or emotional stress. This inherited disease is predominantly caused by mutations in the ryanodine receptor type 2 (RYR2). To minimize the cell line variations for disease modeling, we generated two induced pluripotency stem cell lines (hiPSCs: isCPVTA2254V1-2 and isCPVTA2254V1-3) from skin fibroblasts of one CPVT patient carrying the p.A2254V mutation using CytoTune2.0 Sendai virus cocktail for non-integration reprogramming. All generated iPSCs maintained pluripotency, normal karyotype, and spontaneous in vivo and in vitro differentiation capacity.

Published
2021

29. The clinical-phenotype continuum inDYNC1H1-related disorders-genomic profiling and proposal for a novel classification

Author

Becker, Lena-Luise, Dafsari, Hormos Salimi, Schallner, Jens, Abdin, Dalia, Seifert, Michael, Petit, Florence, Smol, Thomas, Bok, Levinus, Rodan, Lance, Krapels, Ingrid, Spranger, Stephanie, Weschke, Bernhard, Johnson, Katherine, Straub, Volker, Kaindl, Angela M., Di Donato, Nataliya, von der Hagen, Maja, Cirak, Sebahattin, Becker, Lena-Luise, Dafsari, Hormos Salimi, Schallner, Jens, Abdin, Dalia, Seifert, Michael, Petit, Florence, Smol, Thomas, Bok, Levinus, Rodan, Lance, Krapels, Ingrid, Spranger, Stephanie, Weschke, Bernhard, Johnson, Katherine, Straub, Volker, Kaindl, Angela M., Di Donato, Nataliya, von der Hagen, Maja, and Cirak, Sebahattin

Abstract

Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenicDYNC1H1variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation ofDYNC1H1. We identified ten patients with nine novel mutations in theDYNC1H1gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation inDYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype-phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength inDYNC1H1-NMD and motor domain with cerebral malformations inDYNC1H1-NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up ofDYNC1H1-related disorders. We propose a novel clinical classification forDYNC1H1-related disorders encompassing a spectrum fromDYNC1H1-NMD with an exclusive PNS phenotype toDYNC1H1-NDD with concomitant CNS involvement.

Published
2020

30. International consensus recommendations on the diagnostic work-up for malformations of cortical development

Author

Genetica, Genetica Klinische Genetica, Brain, Child Health, Pathologie, Oegema, Renske, Barakat, Tahsin Stefan, Wilke, Martina, Stouffs, Katrien, Amrom, Dina, Aronica, Eleonora, Bahi-Buisson, Nadia, Conti, Valerio, Fry, Andrew E, Geis, Tobias, Andres, David Gomez, Parrini, Elena, Pogledic, Ivana, Said, Edith, Soler, Doriette, Valor, Luis M, Zaki, Maha S, Mirzaa, Ghayda, Dobyns, William B, Reiner, Orly, Guerrini, Renzo, Pilz, Daniela T, Hehr, Ute, Leventer, Richard J, Jansen, Anna C, Mancini, Grazia M S, Di Donato, Nataliya, Genetica, Genetica Klinische Genetica, Brain, Child Health, Pathologie, Oegema, Renske, Barakat, Tahsin Stefan, Wilke, Martina, Stouffs, Katrien, Amrom, Dina, Aronica, Eleonora, Bahi-Buisson, Nadia, Conti, Valerio, Fry, Andrew E, Geis, Tobias, Andres, David Gomez, Parrini, Elena, Pogledic, Ivana, Said, Edith, Soler, Doriette, Valor, Luis M, Zaki, Maha S, Mirzaa, Ghayda, Dobyns, William B, Reiner, Orly, Guerrini, Renzo, Pilz, Daniela T, Hehr, Ute, Leventer, Richard J, Jansen, Anna C, Mancini, Grazia M S, and Di Donato, Nataliya

Published
2020

31. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle

Author

Deardorff, Matthew A., Bando, Masashige, Nakato, Ryuichiro, Watrin, Erwan, Itoh, Takehiko, Minamino, Masashi, Saitoh, Katsuya, Komata, Makiko, Katou, Yuki, Clark, Dinah, Cole, Kathryn E., De Baere, Elfride, Decroos, Christophe, Di Donato, Nataliya, Ernst, Sarah, Francey, Lauren J., Gyftodimou, Yolanda, Hirashima, Kyotaro, Hullings, Melanie, Ishikawa, Yuuichi, Jaulin, Christian, Kaur, Maninder, Kiyono, Tohru, Lombardi, Patrick M., Magnaghi-Jaulin, Laura, Mortier, Geert R., Nozaki, Naohito, Petersen, Michael B., Seimiya, Hiroyuki, Siu, Victoria M., Suzuki, Yutaka, Takagaki, Kentaro, Wilde, Jonathan J., Willems, Patrick J., Prigent, Claude, Gillessen-Kaesbach, Gabriele, Christianson, David W., Kaiser, Frank J., Jackson, Laird G., Hirota, Toru, Krantz, Ian D., and Shirahige, Katsuhiko

Published
2012
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32. Correction: Diagnostic value of partial exome sequencing in developmental disorders

Author

Gieldon, Laura, primary, Mackenroth, Luisa, additional, Kahlert, Anne-Karin, additional, Lemke, Johannes R., additional, Porrmann, Joseph, additional, Schallner, Jens, additional, von der Hagen, Maja, additional, Markus, Susanne, additional, Weidensee, Sabine, additional, Novotna, Barbara, additional, Soerensen, Charlotte, additional, Klink, Barbara, additional, Wagner, Johannes, additional, Tzschach, Andreas, additional, Jahn, Arne, additional, Kuhlee, Franziska, additional, Hackmann, Karl, additional, Schrock, Evelin, additional, Di Donato, Nataliya, additional, and Rump, Andreas, additional

Published
2020
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33. Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development

Author

Lennox, Ashley L., primary, Hoye, Mariah L., additional, Jiang, Ruiji, additional, Johnson-Kerner, Bethany L., additional, Suit, Lindsey A., additional, Venkataramanan, Srivats, additional, Sheehan, Charles J., additional, Alsina, Fernando C., additional, Fregeau, Brieana, additional, Aldinger, Kimberly A., additional, Moey, Ching, additional, Lobach, Iryna, additional, Afenjar, Alexandra, additional, Babovic-Vuksanovic, Dusica, additional, Bézieau, Stéphane, additional, Blackburn, Patrick R., additional, Bunt, Jens, additional, Burglen, Lydie, additional, Campeau, Philippe M., additional, Charles, Perrine, additional, Chung, Brian H.Y., additional, Cogné, Benjamin, additional, Curry, Cynthia, additional, D’Agostino, Maria Daniela, additional, Di Donato, Nataliya, additional, Faivre, Laurence, additional, Héron, Delphine, additional, Innes, A. Micheil, additional, Isidor, Bertrand, additional, Keren, Boris, additional, Kimball, Amy, additional, Klee, Eric W., additional, Kuentz, Paul, additional, Küry, Sébastien, additional, Martin-Coignard, Dominique, additional, Mirzaa, Ghayda, additional, Mignot, Cyril, additional, Miyake, Noriko, additional, Matsumoto, Naomichi, additional, Fujita, Atsushi, additional, Nava, Caroline, additional, Nizon, Mathilde, additional, Rodriguez, Diana, additional, Blok, Lot Snijders, additional, Thauvin-Robinet, Christel, additional, Thevenon, Julien, additional, Vincent, Marie, additional, Ziegler, Alban, additional, Dobyns, William, additional, Richards, Linda J., additional, Barkovich, A. James, additional, Floor, Stephen N., additional, Silver, Debra L., additional, and Sherr, Elliott H., additional

Published
2020
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34. Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment

Author

Fiordaliso, Sarah K., primary, Iwata-Otsubo, Aiko, additional, Ritter, Alyssa L., additional, Quesnel-Vallières, Mathieu, additional, Fujiki, Katsunori, additional, Nishi, Eriko, additional, Hancarova, Miroslava, additional, Miyake, Noriko, additional, Morton, Jenny E.V., additional, Lee, Sangmoon, additional, Hackmann, Karl, additional, Bando, Masashige, additional, Masuda, Koji, additional, Nakato, Ryuichiro, additional, Arakawa, Michiko, additional, Bhoj, Elizabeth, additional, Li, Dong, additional, Hakonarson, Hakon, additional, Takeda, Ryojun, additional, Harr, Margaret, additional, Keena, Beth, additional, Zackai, Elaine H., additional, Okamoto, Nobuhiko, additional, Mizuno, Seiji, additional, Ko, Jung Min, additional, Valachova, Alica, additional, Prchalova, Darina, additional, Vlckova, Marketa, additional, Pippucci, Tommaso, additional, Seiler, Christoph, additional, Choi, Murim, additional, Matsumoto, Naomichi, additional, Di Donato, Nataliya, additional, Barash, Yoseph, additional, Sedlacek, Zdenek, additional, Shirahige, Katsuhiko, additional, and Izumi, Kosuke, additional

Published
2019
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35. Diagnostic value of partial exome sequencing in developmental disorders

Author

Gieldon, Laura, Mackenroth, Luisa, Kahlert, Anne-Karin, Lemke, Johannes R., Porrmann, Joseph, Schallner, Jens, von der Hagen, Maja, Markus, Susanne, Weidensee, Sabine, Novotna, Barbara, Soerensen, Charlotte, Klink, Barbara, Wagner, Johannes, Tzschach, Andreas, Jahn, Arne, Kuhlee, Franziska, Hackmann, Karl, Schrock, Evelin, Di Donato, Nataliya, and Rump, Andreas

Subjects
Male, Molecular biology, Imaging Techniques, Developmental Disabilities, DNA Mutational Analysis, Gene Identification and Analysis, lcsh:Medicine, Gene Sequencing, Genes, Recessive, Nervous System Malformations, Research and Analysis Methods, Diagnostic Radiology, Cohort Studies, Sequencing techniques, Autosomal Recessive Diseases, Pregnancy, Diagnostic Medicine, Intellectual Disability, Exome Sequencing, Medicine and Health Sciences, Genetics, Humans, Abnormalities, Multiple, Exome, DNA sequencing, lcsh:Science, Child, Mutation Detection, Clinical Genetics, Biology and life sciences, Radiology and Imaging, lcsh:R, Genetic Variation, Human Genetics, Sequence Analysis, DNA, Syndrome, Magnetic Resonance Imaging, Phenotype, Molecular biology techniques, Genetic Diseases, Face, Mutation, lcsh:Q, Female, Anatomy, Head, Research Article
Abstract

Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.

Published
2018

36. De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders

Author

Dulovic-Mahlow, Marija, primary, Trinh, Joanne, additional, Kandaswamy, Krishna Kumar, additional, Braathen, Geir Julius, additional, Di Donato, Nataliya, additional, Rahikkala, Elisa, additional, Beblo, Skadi, additional, Werber, Martin, additional, Krajka, Victor, additional, Busk, Øyvind L., additional, Baumann, Hauke, additional, Al-Sannaa, Nouriya Abbas, additional, Hinrichs, Frauke, additional, Affan, Rabea, additional, Navot, Nir, additional, Al Balwi, Mohammed A., additional, Oprea, Gabriela, additional, Holla, Øystein L., additional, Weiss, Maximilian E.R., additional, Jamra, Rami A., additional, Kahlert, Anne-Karin, additional, Kishore, Shivendra, additional, Tveten, Kristian, additional, Vos, Melissa, additional, Rolfs, Arndt, additional, and Lohmann, Katja, additional

Published
2019
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37. Parental mosaicism in epilepsies due to alleged de novo variants

Author

Møller, Rikke S., primary, Liebmann, Nora, additional, Larsen, Line H. G., additional, Stiller, Mathias, additional, Hentschel, Julia, additional, Kako, Nahrain, additional, Abdin, Dalia, additional, Di Donato, Nataliya, additional, Pal, Deb K., additional, Zacher, Pia, additional, Syrbe, Steffen, additional, Dahl, Hans A., additional, and Lemke, Johannes R., additional

Published
2019
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38. De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies

Author

Platzer, Konrad, primary, Sticht, Heinrich, additional, Edwards, Stacey L., additional, Allen, William, additional, Angione, Kaitlin M., additional, Bonati, Maria T., additional, Brasington, Campbell, additional, Cho, Megan T., additional, Demmer, Laurie A., additional, Falik-Zaccai, Tzipora, additional, Gamble, Candace N., additional, Hellenbroich, Yorck, additional, Iascone, Maria, additional, Kok, Fernando, additional, Mahida, Sonal, additional, Mandel, Hanna, additional, Marquardt, Thorsten, additional, McWalter, Kirsty, additional, Panis, Bianca, additional, Pepler, Alexander, additional, Pinz, Hailey, additional, Ramos, Luiza, additional, Shinde, Deepali N., additional, Smith-Hicks, Constance, additional, Stegmann, Alexander P.A., additional, Stöbe, Petra, additional, Stumpel, Constance T.R.M., additional, Wilson, Carolyn, additional, Lemke, Johannes R., additional, Di Donato, Nataliya, additional, Miller, Kenneth G., additional, and Jamra, Rami, additional

Published
2019
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39. A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73

Author

Eisenberger, Tobias, Di Donato, Nataliya, Decker, Christian, Delle Vedove, Andrea, Neuhaus, Christine, Nuernberg, Gudrun, Toliat, Mohammad, Nuernberg, Peter, Muerbe, Dirk, Bolz, Hanno Joern, Eisenberger, Tobias, Di Donato, Nataliya, Decker, Christian, Delle Vedove, Andrea, Neuhaus, Christine, Nuernberg, Gudrun, Toliat, Mohammad, Nuernberg, Peter, Muerbe, Dirk, and Bolz, Hanno Joern

Abstract

Purpose: Hearing loss is genetically extremely heterogeneous, making it suitable for next-generation sequencing (NGS). We identified a four-generation family with nonsyndromic mild to severe hearing loss of the mid-to high frequencies and onset from early childhood to second decade in seven members. Methods: NGS of 66 deafness genes, Sanger sequencing, genome-wide linkage analysis, whole-exome sequencing (WES), semiquantitative reverse-transcriptase polymerase chain reaction. Results: We identified a heterozygous nonsense mutation, c.6881G> A (p.Trp2294*), in the last coding exon of PTPRQ. PTPRQ has been linked with recessive (DFNB84A), but not dominant deafness. NGS and Sanger sequencing of all exons (including alternatively spliced 5' and N-scan-predicted exons of a putative extended transcript) did not identify a second mutation. The highest logarithm of the odds score was in the PTPRQ-containing region on chromosome 12, and p.Trp2294* cosegregated with hearing loss. WES did not identify other cosegregating candidate variants from the mapped region. PTPRQ expression in patient fibroblasts indicated that the mutant allele escapes nonsense-mediated decay (NMD). Conclusion: Known PTPRQ mutations are recessive and do not affect the C-terminal exon. In contrast to recessive loss-of-function mutations, c.6881G> A transcripts may escape NMD. PTPRQ(Trp2294*) protein would lack only six terminal residues and could exert a dominant-negative effect, a possible explanation for allelic deafness, DFNA73, clinically and genetically distinct from DFNB84A.

Published
2018

40. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, Rocio, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah A, van Dam, Sipko, Hoover-Fong, Julie, Telegrafi, Aida B, Destree, Anne, Smigiel, Robert, Lambie, Lindsday A, Kayserili, Hülya, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G, Mihci, Ercan, Moreira, Lilia M A, Borges Ferreira, Viviane, Horovitz, Dafne D G, da Rocha, Katia M, Jezela-Stanek, Aleksandra, Brooks, Alice S, Reutter, Heiko, Cohen, Julie S, Fatemi, Ali, Smitka, Martin, Grebe, Theresa A, Di Donato, Nataliya, et al, and University of Zurich

Subjects
2716 Genetics (clinical), 1105 Ecology, Evolution, Behavior and Systematics, 1311 Genetics, 10039 Institute of Medical Genetics, 1312 Molecular Biology, 570 Life sciences, biology, 610 Medicine & health, 1306 Cancer Research
Published
2017

42. Biallelic UBE4Aloss-of-function variants cause intellectual disability and global developmental delay

Author

Melo, Uirá Souto, Bonner, Devon, Kent Lloyd, Kevin C., Moshiri, Ala, Willis, Brandon, Lanoue, Louise, Bower, Lynette, Leonard, Brian C., Martins, Davi Jardim, Gomes, Fernando, de Souza Leite, Felipe, Oliveira, Danyllo, Kitajima, João Paulo, Monteiro, Fabiola P., Zatz, Mayana, Menck, Carlos Frederico Martins, Wheeler, Matthew T., Bernstein, Jonathan A., Dumas, Kevin, Spiteri, Elizabeth, Di Donato, Nataliya, Jahn, Arne, Hashem, Mais, Alsaif, Hessa S., Chedrawi, Aziza, Alkuraya, Fowzan S., Kok, Fernando, and Byers, Heather M.

Abstract

To identify novel genes associated with intellectual disability (ID) in four unrelated families.

Published
2021
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43. Novel PRPS1 gain-of-function mutation in a patient with congenital hyperuricemia and facial anomalies

Author

Porrmann, Joseph, Betcheva-Krajcir, Elitza, Di Donato, Nataliya, Kahlert, Anne-Karin, Schallner, Jens, Rump, Andreas, Schroeck, Evelin, Dobritzsch, Doreen, Roelofsen, Jeroen, van Kuilenburg, Andre B. P., Tzschach, Andreas, Porrmann, Joseph, Betcheva-Krajcir, Elitza, Di Donato, Nataliya, Kahlert, Anne-Karin, Schallner, Jens, Rump, Andreas, Schroeck, Evelin, Dobritzsch, Doreen, Roelofsen, Jeroen, van Kuilenburg, Andre B. P., and Tzschach, Andreas

Abstract

Phosphoribosylpyrophosphate synthetase (PRPPS) superactivity (OMIM 300661) is a rare inborn error of purine metabolism that is caused by gain-of-function mutations in the X-chromosomal gene PRPS1 (Xq22.3). Clinical characteristics include congenital hyperuricemia and hyperuricosuria, gouty arthritis, urolithiasis, developmental delay, hypotonia, recurrent infections, short stature, and hearing loss. Only eight families with PRPPS superactivity and PRPS1 gain-of-function mutations have been reported to date. We report on a 7-year-old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here broadens the clinical spectrum of PRPPS superactivity and indicates that this rare metabolic disorder might be associated with a recognizable facial gestalt.

Published
2017
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44. GRIN2B encephalopathy : Novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Author

Platzer, Konrad, Yuan, Hongjie, Schütz, Hannah, Winschel, Alexander, Chen, Wenjuan, Hu, Chun, Kusumoto, Hirofumi, Heyne, Henrike O, Helbig, Katherine L, Tang, Sha, Willing, Marcia C, Tinkle, Brad T, Adams, Darius J, Depienne, Christel, Keren, Boris, Mignot, Cyril, Frengen, Eirik, Strømme, Petter, Biskup, Saskia, Döcker, Dennis, Strom, Tim M., Mefford, Heather C., Myers, Candace T., Muir, Alison M, LaCroix, Amy, Sadleir, Lynette G., Scheffer, Ingrid E., Brilstra, Eva, van Haelst, Mieke M., van der Smagt, Jasper J., Bok, Levinus A, Møller, Rikke S., Jensen, Uffe Birk, Millichap, John J, Berg, Anne T, Goldberg, Ethan M, De Bie, Isabelle, Fox, Stephanie, Major, Philippe, Jones, Julie R, Zackai, Elaine H., Abou Jamra, Rami, Rolfs, Arndt, Leventer, Richard J, Lawson, John A, Roscioli, Tony, Jansen, Floor E., Ranza, Emmanuelle, Korff, Christian M, Lehesjoki, Anna-Elina, Courage, Carolina, Linnankivi, Tarja, Smith, Douglas R, Stanley, Christine, Mintz, Mark, McKnight, Dianalee, Decker, Amy, Tan, Wen-Hann, Tarnopolsky, Mark A, Brady, Lauren I, Wolff, Markus, Dondit, Lutz, Pedro, Helio F, Parisotto, Sarah E, Jones, Kelly L, Patel, Anup D, Franz, David N, Vanzo, Rena, Marco, Elysa, Ranells, Judith D, Di Donato, Nataliya, Dobyns, William B., Laube, Bodo, Traynelis, Stephen F, Lemke, Johannes R., Platzer, Konrad, Yuan, Hongjie, Schütz, Hannah, Winschel, Alexander, Chen, Wenjuan, Hu, Chun, Kusumoto, Hirofumi, Heyne, Henrike O, Helbig, Katherine L, Tang, Sha, Willing, Marcia C, Tinkle, Brad T, Adams, Darius J, Depienne, Christel, Keren, Boris, Mignot, Cyril, Frengen, Eirik, Strømme, Petter, Biskup, Saskia, Döcker, Dennis, Strom, Tim M., Mefford, Heather C., Myers, Candace T., Muir, Alison M, LaCroix, Amy, Sadleir, Lynette G., Scheffer, Ingrid E., Brilstra, Eva, van Haelst, Mieke M., van der Smagt, Jasper J., Bok, Levinus A, Møller, Rikke S., Jensen, Uffe Birk, Millichap, John J, Berg, Anne T, Goldberg, Ethan M, De Bie, Isabelle, Fox, Stephanie, Major, Philippe, Jones, Julie R, Zackai, Elaine H., Abou Jamra, Rami, Rolfs, Arndt, Leventer, Richard J, Lawson, John A, Roscioli, Tony, Jansen, Floor E., Ranza, Emmanuelle, Korff, Christian M, Lehesjoki, Anna-Elina, Courage, Carolina, Linnankivi, Tarja, Smith, Douglas R, Stanley, Christine, Mintz, Mark, McKnight, Dianalee, Decker, Amy, Tan, Wen-Hann, Tarnopolsky, Mark A, Brady, Lauren I, Wolff, Markus, Dondit, Lutz, Pedro, Helio F, Parisotto, Sarah E, Jones, Kelly L, Patel, Anup D, Franz, David N, Vanzo, Rena, Marco, Elysa, Ranells, Judith D, Di Donato, Nataliya, Dobyns, William B., Laube, Bodo, Traynelis, Stephen F, and Lemke, Johannes R.

Published
2017

45. GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Author

Genetica, Genetica Klinische Genetica, Brain, Circulatory Health, ZL Kinder Ner en Nec Medisch, Platzer, Konrad, Yuan, Hongjie, Schütz, Hannah, Winschel, Alexander, Chen, Wenjuan, Hu, Chun, Kusumoto, Hirofumi, Heyne, Henrike O, Helbig, Katherine L, Tang, Sha, Willing, Marcia C, Tinkle, Brad T, Adams, Darius J, Depienne, Christel, Keren, Boris, Mignot, Cyril, Frengen, Eirik, Strømme, Petter, Biskup, Saskia, Döcker, Dennis, Strom, Tim M., Mefford, Heather C., Myers, Candace T., Muir, Alison M, LaCroix, Amy, Sadleir, Lynette G., Scheffer, Ingrid E., Brilstra, Eva, van Haelst, Mieke M., van der Smagt, Jasper J., Bok, Levinus A, Møller, Rikke S., Jensen, Uffe Birk, Millichap, John J, Berg, Anne T, Goldberg, Ethan M, De Bie, Isabelle, Fox, Stephanie, Major, Philippe, Jones, Julie R, Zackai, Elaine H., Abou Jamra, Rami, Rolfs, Arndt, Leventer, Richard J, Lawson, John A, Roscioli, Tony, Jansen, Floor E., Ranza, Emmanuelle, Korff, Christian M, Lehesjoki, Anna-Elina, Courage, Carolina, Linnankivi, Tarja, Smith, Douglas R, Stanley, Christine, Mintz, Mark, McKnight, Dianalee, Decker, Amy, Tan, Wen-Hann, Tarnopolsky, Mark A, Brady, Lauren I, Wolff, Markus, Dondit, Lutz, Pedro, Helio F, Parisotto, Sarah E, Jones, Kelly L, Patel, Anup D, Franz, David N, Vanzo, Rena, Marco, Elysa, Ranells, Judith D, Di Donato, Nataliya, Dobyns, William B., Laube, Bodo, Traynelis, Stephen F, Lemke, Johannes R., Genetica, Genetica Klinische Genetica, Brain, Circulatory Health, ZL Kinder Ner en Nec Medisch, Platzer, Konrad, Yuan, Hongjie, Schütz, Hannah, Winschel, Alexander, Chen, Wenjuan, Hu, Chun, Kusumoto, Hirofumi, Heyne, Henrike O, Helbig, Katherine L, Tang, Sha, Willing, Marcia C, Tinkle, Brad T, Adams, Darius J, Depienne, Christel, Keren, Boris, Mignot, Cyril, Frengen, Eirik, Strømme, Petter, Biskup, Saskia, Döcker, Dennis, Strom, Tim M., Mefford, Heather C., Myers, Candace T., Muir, Alison M, LaCroix, Amy, Sadleir, Lynette G., Scheffer, Ingrid E., Brilstra, Eva, van Haelst, Mieke M., van der Smagt, Jasper J., Bok, Levinus A, Møller, Rikke S., Jensen, Uffe Birk, Millichap, John J, Berg, Anne T, Goldberg, Ethan M, De Bie, Isabelle, Fox, Stephanie, Major, Philippe, Jones, Julie R, Zackai, Elaine H., Abou Jamra, Rami, Rolfs, Arndt, Leventer, Richard J, Lawson, John A, Roscioli, Tony, Jansen, Floor E., Ranza, Emmanuelle, Korff, Christian M, Lehesjoki, Anna-Elina, Courage, Carolina, Linnankivi, Tarja, Smith, Douglas R, Stanley, Christine, Mintz, Mark, McKnight, Dianalee, Decker, Amy, Tan, Wen-Hann, Tarnopolsky, Mark A, Brady, Lauren I, Wolff, Markus, Dondit, Lutz, Pedro, Helio F, Parisotto, Sarah E, Jones, Kelly L, Patel, Anup D, Franz, David N, Vanzo, Rena, Marco, Elysa, Ranells, Judith D, Di Donato, Nataliya, Dobyns, William B., Laube, Bodo, Traynelis, Stephen F, and Lemke, Johannes R.

Published
2017

46. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, Rocio; https://orcid.org/0000-0001-9413-0348, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah A, van Dam, Sipko; https://orcid.org/0000-0001-9204-0197, Hoover-Fong, Julie, Telegrafi, Aida B, Destree, Anne, Smigiel, Robert, Lambie, Lindsday A, Kayserili, Hülya, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G, Mihci, Ercan, Moreira, Lilia M A, Borges Ferreira, Viviane, Horovitz, Dafne D G, da Rocha, Katia M, Jezela-Stanek, Aleksandra, Brooks, Alice S, Reutter, Heiko, Cohen, Julie S, Fatemi, Ali, Smitka, Martin, Grebe, Theresa A, Di Donato, Nataliya, et al, Acuna-Hidalgo, Rocio; https://orcid.org/0000-0001-9413-0348, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah A, van Dam, Sipko; https://orcid.org/0000-0001-9204-0197, Hoover-Fong, Julie, Telegrafi, Aida B, Destree, Anne, Smigiel, Robert, Lambie, Lindsday A, Kayserili, Hülya, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G, Mihci, Ercan, Moreira, Lilia M A, Borges Ferreira, Viviane, Horovitz, Dafne D G, da Rocha, Katia M, Jezela-Stanek, Aleksandra, Brooks, Alice S, Reutter, Heiko, Cohen, Julie S, Fatemi, Ali, Smitka, Martin, Grebe, Theresa A, Di Donato, Nataliya, and et al

Abstract

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Published
2017

47. GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Author

Platzer, Konrad, primary, Yuan, Hongjie, additional, Schütz, Hannah, additional, Winschel, Alexander, additional, Chen, Wenjuan, additional, Hu, Chun, additional, Kusumoto, Hirofumi, additional, Heyne, Henrike O, additional, Helbig, Katherine L, additional, Tang, Sha, additional, Willing, Marcia C, additional, Tinkle, Brad T, additional, Adams, Darius J, additional, Depienne, Christel, additional, Keren, Boris, additional, Mignot, Cyril, additional, Frengen, Eirik, additional, Strømme, Petter, additional, Biskup, Saskia, additional, Döcker, Dennis, additional, Strom, Tim M, additional, Mefford, Heather C, additional, Myers, Candace T, additional, Muir, Alison M, additional, LaCroix, Amy, additional, Sadleir, Lynette, additional, Scheffer, Ingrid E, additional, Brilstra, Eva, additional, van Haelst, Mieke M, additional, van der Smagt, Jasper J, additional, Bok, Levinus A, additional, Møller, Rikke S, additional, Jensen, Uffe B, additional, Millichap, John J, additional, Berg, Anne T, additional, Goldberg, Ethan M, additional, De Bie, Isabelle, additional, Fox, Stephanie, additional, Major, Philippe, additional, Jones, Julie R, additional, Zackai, Elaine H, additional, Abou Jamra, Rami, additional, Rolfs, Arndt, additional, Leventer, Richard J, additional, Lawson, John A, additional, Roscioli, Tony, additional, Jansen, Floor E, additional, Ranza, Emmanuelle, additional, Korff, Christian M, additional, Lehesjoki, Anna-Elina, additional, Courage, Carolina, additional, Linnankivi, Tarja, additional, Smith, Douglas R, additional, Stanley, Christine, additional, Mintz, Mark, additional, McKnight, Dianalee, additional, Decker, Amy, additional, Tan, Wen-Hann, additional, Tarnopolsky, Mark A, additional, Brady, Lauren I, additional, Wolff, Markus, additional, Dondit, Lutz, additional, Pedro, Helio F, additional, Parisotto, Sarah E, additional, Jones, Kelly L, additional, Patel, Anup D, additional, Franz, David N, additional, Vanzo, Rena, additional, Marco, Elysa, additional, Ranells, Judith D, additional, Di Donato, Nataliya, additional, Dobyns, William B, additional, Laube, Bodo, additional, Traynelis, Stephen F, additional, and Lemke, Johannes R, additional

Published
2017
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48. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, Rocio, primary, Deriziotis, Pelagia, additional, Steehouwer, Marloes, additional, Gilissen, Christian, additional, Graham, Sarah A., additional, van Dam, Sipko, additional, Hoover-Fong, Julie, additional, Telegrafi, Aida B., additional, Destree, Anne, additional, Smigiel, Robert, additional, Lambie, Lindsday A., additional, Kayserili, Hülya, additional, Altunoglu, Umut, additional, Lapi, Elisabetta, additional, Uzielli, Maria Luisa, additional, Aracena, Mariana, additional, Nur, Banu G., additional, Mihci, Ercan, additional, Moreira, Lilia M. A., additional, Borges Ferreira, Viviane, additional, Horovitz, Dafne D. G., additional, da Rocha, Katia M., additional, Jezela-Stanek, Aleksandra, additional, Brooks, Alice S., additional, Reutter, Heiko, additional, Cohen, Julie S., additional, Fatemi, Ali, additional, Smitka, Martin, additional, Grebe, Theresa A., additional, Di Donato, Nataliya, additional, Deshpande, Charu, additional, Vandersteen, Anthony, additional, Marques Lourenço, Charles, additional, Dufke, Andreas, additional, Rossier, Eva, additional, Andre, Gwenaelle, additional, Baumer, Alessandra, additional, Spencer, Careni, additional, McGaughran, Julie, additional, Franke, Lude, additional, Veltman, Joris A., additional, De Vries, Bert B. A., additional, Schinzel, Albert, additional, Fisher, Simon E., additional, Hoischen, Alexander, additional, and van Bon, Bregje W., additional

Published
2017
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49. Constitutional de novo and postzygotic mutations in isolated cases of cerebral cavernous malformations

Author

Rath, Matthias, primary, Spiegler, Stefanie, additional, Nath, Neetika, additional, Schwefel, Konrad, additional, Di Donato, Nataliya, additional, Gerber, Johannes, additional, Korenke, G. Christoph, additional, Hellenbroich, Yorck, additional, Hehr, Ute, additional, Gross, Stephanie, additional, Sure, Ulrich, additional, Zoll, Barbara, additional, Gilberg, Eberhard, additional, Kaderali, Lars, additional, and Felbor, Ute, additional

Published
2016
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50. Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant

Author

Di Donato, Nataliya, primary, Jean, Ying Y., additional, Maga, A. Murat, additional, Krewson, Briana D., additional, Shupp, Alison B., additional, Avrutsky, Maria I., additional, Roy, Achira, additional, Collins, Sarah, additional, Olds, Carissa, additional, Willert, Rebecca A., additional, Czaja, Agnieszka M., additional, Johnson, Rachel, additional, Stover, Jessi A., additional, Gottlieb, Steven, additional, Bartholdi, Deborah, additional, Rauch, Anita, additional, Goldstein, Amy, additional, Boyd-Kyle, Victoria, additional, Aldinger, Kimberly A., additional, Mirzaa, Ghayda M., additional, Nissen, Anke, additional, Brigatti, Karlla W., additional, Puffenberger, Erik G., additional, Millen, Kathleen J., additional, Strauss, Kevin A., additional, Dobyns, William B., additional, Troy, Carol M., additional, and Jinks, Robert N., additional

Published
2016
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