2,948 results on '"Lupski, James R."'
Search Results
2. Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus
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Daly, Adrian F., Dunnington, Leslie A., Rodriguez-Buritica, David F., Spiegel, Erica, Brancati, Francesco, Mantovani, Giovanna, Rawal, Vandana M., Faucz, Fabio Rueda, Hijazi, Hadia, Caberg, Jean-Hubert, Nardone, Anna Maria, Bengala, Mario, Fortugno, Paola, Del Sindaco, Giulia, Ragonese, Marta, Gould, Helen, Cannavò, Salvatore, Pétrossians, Patrick, Lania, Andrea, Lupski, James R., Beckers, Albert, Stratakis, Constantine A., Levy, Brynn, Trivellin, Giampaolo, and Franke, Martin
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- 2024
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3. Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy
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Banks, Emily, Francis, Vincent, Lin, Sheng-Jia, Kharfallah, Fares, Fonov, Vladimir, Lévesque, Maxime, Han, Chanshuai, Kulasekaran, Gopinath, Tuznik, Marius, Bayati, Armin, Al-Khater, Reem, Alkuraya, Fowzan S., Argyriou, Loukas, Babaei, Meisam, Bahlo, Melanie, Bakhshoodeh, Behnoosh, Barr, Eileen, Bartik, Lauren, Bassiony, Mahmoud, Bertrand, Miriam, Braun, Dominique, Buchert, Rebecca, Budetta, Mauro, Cadieux-Dion, Maxime, Calame, Daniel G., Cope, Heidi, Cushing, Donna, Efthymiou, Stephanie, Elmaksoud, Marwa Abd, El Said, Huda G., Froukh, Tawfiq, Gill, Harinder K., Gleeson, Joseph G., Gogoll, Laura, Goh, Elaine S.-Y., Gowda, Vykuntaraju K., Haack, Tobias B., Hashem, Mais O., Hauser, Stefan, Hoffman, Trevor L., Hogue, Jacob S., Hosokawa, Akimoto, Houlden, Henry, Huang, Kevin, Huynh, Stephanie, Karimiani, Ehsan G., Kaulfuß, Silke, Korenke, G. Christoph, Kritzer, Amy, Lee, Hane, Lupski, James R., Marco, Elysa J., McWalter, Kirsty, Minassian, Arakel, Minassian, Berge A., Murphy, David, Neira-Fresneda, Juanita, Northrup, Hope, Nyaga, Denis M., Oehl-Jaschkowitz, Barbara, Osmond, Matthew, Person, Richard, Pehlivan, Davut, Petree, Cassidy, Sadleir, Lynette G., Saunders, Carol, Schoels, Ludger, Shashi, Vandana, Spillmann, Rebecca C., Srinivasan, Varunvenkat M., Torbati, Paria N., Tos, Tulay, Zaki, Maha S., Zhou, Dihong, Zweier, Christiane, Trempe, Jean-François, Durcan, Thomas M., Gan-Or, Ziv, Avoli, Massimo, Alves, Cesar, Varshney, Gaurav K., Maroofian, Reza, Rudko, David A., and McPherson, Peter S.
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- 2024
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4. Correction: Multilocus pathogenic variants contribute to intrafamilial clinical heterogeneity: a retrospective study of sibling pairs with neurodevelopmental disorders
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Bozkurt‑Yozgatli, Tugce, Pehlivan, Davut, Gibbs, Richard A., Sezerman, Ugur, Posey, Jennifer E., Lupski, James R., and Coban‑Akdemir, Zeynep
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- 2024
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5. Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles
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Bassani, Sissy, Chrast, Jacqueline, Ambrosini, Giovanna, Voisin, Norine, Schütz, Frédéric, Brusco, Alfredo, Sirchia, Fabio, Turban, Lydia, Schubert, Susanna, Abou Jamra, Rami, Schlump, Jan-Ulrich, DeMille, Desiree, Bayrak-Toydemir, Pinar, Nelson, Gary Rex, Wong, Kristen Nicole, Duncan, Laura, Mosera, Mackenzie, Gilissen, Christian, Vissers, Lisenka E. L. M., Pfundt, Rolph, Kersseboom, Rogier, Yttervik, Hilde, Hansen, Geir Åsmund Myge, Smeland, Marie Falkenberg, Butler, Kameryn M., Lyons, Michael J., Carvalho, Claudia M. B., Zhang, Chaofan, Lupski, James R., Potocki, Lorraine, Flores-Gallegos, Leticia, Morales-Toquero, Rodrigo, Petit, Florence, Yalcin, Binnaz, Tuttle, Annabelle, Elloumi, Houda Zghal, McCormick, Lane, Kukolich, Mary, Klaas, Oliver, Horvath, Judit, Scala, Marcello, Iacomino, Michele, Operto, Francesca, Zara, Federico, Writzl, Karin, Maver, Aleš, Haanpää, Maria K., Pohjola, Pia, Arikka, Harri, Kievit, Anneke J. A., Calandrini, Camilla, Iseli, Christian, Guex, Nicolas, and Reymond, Alexandre
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- 2024
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6. Multilocus pathogenic variants contribute to intrafamilial clinical heterogeneity: a retrospective study of sibling pairs with neurodevelopmental disorders
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Bozkurt-Yozgatli, Tugce, Pehlivan, Davut, Gibbs, Richard A., Sezerman, Ugur, Posey, Jennifer E., Lupski, James R., and Coban-Akdemir, Zeynep
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- 2024
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7. NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy
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Dardas, Zain, Fatih, Jawid M., Jolly, Angad, Dawood, Moez, Du, Haowei, Grochowski, Christopher M., Jones, Edward G., Jhangiani, Shalini N., Wehrens, Xander H. T., Liu, Pengfei, Bi, Weimin, Boerwinkle, Eric, Posey, Jennifer E., Muzny, Donna M., Gibbs, Richard A., Lupski, James R., Coban-Akdemir, Zeynep, and Morris, Shaine A.
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- 2024
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8. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies
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Stegmann, Jil D., Kalanithy, Jeshurun C., Dworschak, Gabriel C., Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M., Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T., Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J., Klee, Eric W., Lanpher, Brendan C., Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R., Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L., Riley, Kacie, Klee, Victoria, Walsh, Laurence E., Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stoppe, Arzu, Stuurman, Kyra, van Slegtenhorst, Marjon, Barakat, Tahsin Stefan, Mulhern, Maureen S., Sands, Tristan T., Cytrynbaum, Cheryl, Weksberg, Rosanna, Isidori, Federica, Pippucci, Tommaso, Severi, Giulia, Montanari, Francesca, Kruer, Michael C., Bakhtiari, Somayeh, Darvish, Hossein, Reutter, Heiko, Hagelueken, Gregor, Geyer, Matthias, Woolf, Adrian S., Posey, Jennifer E., Lupski, James R., Odermatt, Benjamin, and Hilger, Alina C.
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- 2024
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9. Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta
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Caron, Véronique, Chassaing, Nicolas, Ragge, Nicola, Boschann, Felix, Ngu, Angelina My-Hoa, Meloche, Elisabeth, Chorfi, Sarah, Lakhani, Saquib A, Ji, Weizhen, Steiner, Laurie, Marcadier, Julien, Jansen, Philip R, van de Pol, Laura A, van Hagen, Johanna M, Russi, Alvaro Serrano, Le Guyader, Gwenaël, Nordenskjöld, Magnus, Nordgren, Ann, Anderlid, Britt-Marie, Plaisancié, Julie, Stoltenburg, Corinna, Horn, Denise, Drenckhahn, Anne, Hamdan, Fadi F, Lefebvre, Mathilde, Attie-Bitach, Tania, Forey, Peggy, Smirnov, Vasily, Ernould, Françoise, Jacquemont, Marie-Line, Grotto, Sarah, Alcantud, Alberto, Coret, Alicia, Ferrer-Avargues, Rosario, Srivastava, Siddharth, Vincent-Delorme, Catherine, Romoser, Shelby, Safina, Nicole, Saade, Dimah, Lupski, James R, Calame, Daniel G, Geneviève, David, Chatron, Nicolas, Schluth-Bolard, Caroline, Myers, Kenneth A, Dobyns, William B, Calvas, Patrick, Study, The DDD, Salmon, Caroline, Holt, Richard, Elmslie, Frances, Allaire, Marc, Prigozhin, Daniil M, Tremblay, André, and Michaud, Jacques L
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Biological Sciences ,Genetics ,Clinical Research ,Pediatric ,2.1 Biological and endogenous factors ,Aetiology ,Humans ,Receptors ,Retinoic Acid ,Retinoids ,Microphthalmos ,DDD Study ,Dystonia ,Global developmental delay ,Microphthalmia ,Retinoic acid ,Retinoic acid receptor beta ,Clinical Sciences ,Genetics & Heredity - Abstract
PurposeDominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.MethodsWe used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.ResultsWe found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.ConclusionOur study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.
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- 2023
10. Phenotypic and mutational spectrum of ROR2‐related Robinow syndrome
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Lima, Ariadne R, Ferreira, Barbara M, Zhang, Chaofan, Jolly, Angad, Du, Haowei, White, Janson J, Dawood, Moez, Lins, Tulio C, Chiabai, Marcela A, Beusekom, Ellen, Cordoba, Mara S, Rosa, Erica CC Caldas, Kayserili, Hulya, Kimonis, Virginia, Wu, Erica, Mellado, Cecilia, Aggarwal, Vineet, Richieri‐Costa, Antonio, Brunoni, Décio, Canó, Talyta M, Jorge, Alexander AL, Kim, Chong A, Honjo, Rachel, Bertola, Débora R, Dandalo‐Girardi, Raissa M, Bayram, Yavuz, Gezdirici, Alper, Yilmaz‐Gulec, Elif, Gumus, Evren, Yilmaz, Gülay C, Okamoto, Nobuhiko, Ohashi, Hirofumi, Coban–Akdemir, Zeynep, Mitani, Tadahiro, Jhangiani, Shalini N, Muzny, Donna M, Regattieri, Neysa AP, Pogue, Robert, Pereira, Rinaldo W, Otto, Paulo A, Gibbs, Richard A, Ali, Bassam R, Bokhoven, Hans, Brunner, Han G, Sutton, V Reid, Lupski, James R, Vianna‐Morgante, Angela M, Carvalho, Claudia MB, and Mazzeu, Juliana F
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Clinical Research ,Pediatric ,Congenital Structural Anomalies ,Aetiology ,2.1 Biological and endogenous factors ,Craniofacial Abnormalities ,Dwarfism ,Genes ,Recessive ,Humans ,Limb Deformities ,Congenital ,Male ,Phenotype ,Receptor Tyrosine Kinase-like Orphan Receptors ,Urogenital Abnormalities ,chromosome microarray analysis ,craniofacial morphology ,exonic deletion ,HPO terms ,next-generation sequencing ,quantitative phenotyping cluster heatmap ,skeletal dysplasia ,WNT pathway ,Clinical Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.
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- 2022
11. PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response
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Deb, Wallid, Rosenfelt, Cory, Vignard, Virginie, Papendorf, Jonas Johannes, Möller, Sophie, Wendlandt, Martin, Studencka-Turski, Maja, Cogné, Benjamin, Besnard, Thomas, Ruffier, Léa, Toutain, Bérénice, Poirier, Léa, Cuinat, Silvestre, Kritzer, Amy, Crunk, Amy, diMonda, Janette, Vengoechea, Jaime, Mercier, Sandra, Kleinendorst, Lotte, van Haelst, Mieke M., Zuurbier, Linda, Sulem, Telma, Katrínardóttir, Hildigunnur, Friðriksdóttir, Rún, Sulem, Patrick, Stefansson, Kari, Jonsdottir, Berglind, Zeidler, Shimriet, Sinnema, Margje, Stegmann, Alexander P.A., Naveh, Natali, Skraban, Cara M., Gray, Christopher, Murrell, Jill R., Isikay, Sedat, Pehlivan, Davut, Calame, Daniel G., Posey, Jennifer E., Nizon, Mathilde, McWalter, Kirsty, Lupski, James R., Isidor, Bertrand, Bolduc, François V., Bézieau, Stéphane, Krüger, Elke, Küry, Sébastien, and Ebstein, Frédéric
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- 2024
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12. Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci
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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.
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- 2024
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13. Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma
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Ma, Mengqi, Ganapathi, Mythily, Zheng, Yiming, Tan, Kai-Li, Kanca, Oguz, Bove, Kevin E., Quintanilla, Norma, Sag, Sebnem O., Temel, Sehime G., LeDuc, Charles A., McPartland, Amanda J., Pereira, Elaine M., Shen, Yufeng, Hagen, Jacob, Thomas, Christie P., Nguyen Galván, Nhu Thao, Pan, Xueyang, Lu, Shenzhao, Rosenfeld, Jill A., Calame, Daniel G., Wangler, Michael F., Lupski, James R., Pehlivan, Davut, Hertel, Paula M., Chung, Wendy K., and Bellen, Hugo J.
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- 2024
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14. Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals
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Sczakiel, Henrike L., Zhao, Max, Wollert-Wulf, Brigitte, Danyel, Magdalena, Ehmke, Nadja, Stoltenburg, Corinna, Damseh, Nadirah, Al-Ashhab, Motee, Balci, Tugce B., Osmond, Matthew, Andrade, Andrea, Schallner, Jens, Porrmann, Joseph, McDonald, Kimberly, Liao, Mingjuan, Oppermann, Henry, Platzer, Konrad, Dierksen, Nadine, Mojarrad, Majid, Eslahi, Atieh, Bakaeean, Behnaz, Calame, Daniel G., Lupski, James R., Firoozfar, Zahra, Seyedhassani, Seyed Mohammad, Mohammadi, Seyed Ahmad, Anwaar, Najwa, Rahman, Fatima, Seelow, Dominik, Janz, Martin, Horn, Denise, Maroofian, Reza, and Boschann, Felix
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- 2023
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15. Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt
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Shepherdson, James L., Hutchison, Katie, Don, Dilan Wellalage, McGillivray, George, Choi, Tae-Ik, Allan, Carolyn A., Amor, David J., Banka, Siddharth, Basel, Donald G., Buch, Laura D., Carere, Deanna Alexis, Carroll, Renée, Clayton-Smith, Jill, Crawford, Ali, Dunø, Morten, Faivre, Laurence, Gilfillan, Christopher P., Gold, Nina B., Gripp, Karen W., Hobson, Emma, Holtz, Alexander M., Innes, A. Micheil, Isidor, Bertrand, Jackson, Adam, Katsonis, Panagiotis, Amel Riazat Kesh, Leila, Küry, Sébastien, Lecoquierre, François, Lockhart, Paul, Maraval, Julien, Matsumoto, Naomichi, McCarrier, Julie, McCarthy, Josephine, Miyake, Noriko, Moey, Lip Hen, Németh, Andrea H., Østergaard, Elsebet, Patel, Rushina, Pope, Kate, Posey, Jennifer E., Schnur, Rhonda E., Shaw, Marie, Stolerman, Elliot, Taylor, Julie P., Wadman, Erin, Wakeling, Emma, White, Susan M., Wong, Lawrence C., Lupski, James R., Lichtarge, Olivier, Corbett, Mark A., Gecz, Jozef, Nicolet, Charles M., Farnham, Peggy J., Kim, Cheol-Hee, and Shinawi, Marwan
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- 2024
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16. Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability
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Agrawal, Pankaj, Armstrong Scott, Daryl, Barkoudah, Elizabeth, Bellini, Melissa, Beneteau, Claire, Bjørgo, Kathrine, Brooks, Alice, Brown, Natasha, Castle, Alison, Castro, Diana, Chorin, Odelia, Cleghorn, Mark, Clement, Emma, Coman, David, Costin, Carrie, Devriendt, Koen, Dong, Dexin, Dries, Annika, Duelund Hjortshøj, Tina, Dyment, David, Eng, Christine, Genetti, Casie, Grano, Siera, Henneman, Peter, Heron, Delphine, Hoffmann, Katrin, Hom, Jason, Du, Haowei, Iascone, Maria, Isidor, Bertrand, Järvelä, Irma E., Jones, Julie, Keren, Boris, Koenig, Mary Kay, Kohlhase, Jürgen, Lalani, Seema, Le Caignec, Cedric, Lewis, Andi, Liu, Pengfei, Lovgren, Alysia, Lupski, James R., Lyons, Mike, Lysy, Philippe, Manning, Melanie, Marcelis, Carlo, McLean, Scott Douglas, Mercie, Sandra, Mertens, Mareike, Molin, Arnaud, Nizon, Mathilde, Nugent, Kimberly Margaret, Öhman, Susanna, O'Leary, Melanie, Okashah Littlejohn, Rebecca, Petit, Florence, Pfundt, Rolph, Pottocki, Lorraine, Raas-Rotschild, Annick, Ranguin, Kara, Revencu, Nicole, Rosenfeld, Jill, Rhodes, Lindsay, Santos Simmaro, Fernando, Sals, Karen, Schieving, Jolanda, Schrauwen, Isabelle, Schuurs-Hoeijmakers, Janneke H.M., Seaby, Eleanor G., Sheffer, Ruth, Snijders Blok, Lot, Sørensen, Kristina P., Srivastava, Siddharth, Stark, Zornitza, Stoeva, Radka, Stutterd, Chloe, Tan, Natalie B., Mathiesen Torring, Pernille, Vanakker, Olivier, van der Laan, Liselot, Ververi, Athina, Villavicencio-Lorini, Pablo, Vincent, Marie, Wand, Dorothea, Wessels, Marja, White, Sue, Wojcik, Monica H., Wu, Nan, Zhao, Sen, Pérez Baca, María del Rocío, Jacobs, Eva Z., Vantomme, Lies, Leblanc, Pontus, Bogaert, Elke, Dheedene, Annelies, De Cock, Laurenz, Haghshenas, Sadegheh, Foroutan, Aidin, Levy, Michael A., Kerkhof, Jennifer, McConkey, Haley, Chen, Chun-An, Batzir, Nurit Assia, Wang, Xia, Palomares, María, Carels, Marieke, Dermaut, Bart, Sadikovic, Bekim, Menten, Björn, Yuan, Bo, Vergult, Sarah, and Callewaert, Bert
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- 2024
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17. Biallelic variants in SLC4A10 encoding a sodium-dependent bicarbonate transporter lead to a neurodevelopmental disorder
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Maroofian, Reza, Zamani, Mina, Kaiyrzhanov, Rauan, Liebmann, Lutz, Karimiani, Ehsan Ghayoor, Vona, Barbara, Huebner, Antje K., Calame, Daniel G., Misra, Vinod K., Sadeghian, Saeid, Azizimalamiri, Reza, Mohammadi, Mohammad Hasan, Zeighami, Jawaher, Heydaran, Sogand, Toosi, Mehran Beiraghi, Akhondian, Javad, Babaei, Meisam, Hashemi, Narges, Schnur, Rhonda E., Suri, Mohnish, Setzke, Jonas, Wagner, Matias, Brunet, Theresa, Grochowski, Christopher M., Emrick, Lisa, Chung, Wendy K., Hellmich, Ute A., Schmidts, Miriam, Lupski, James R., Galehdari, Hamid, Severino, Mariasavina, Houlden, Henry, and Hübner, Christian A.
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- 2024
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18. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum
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Calame, Daniel G., Wong, Jovi Huixin, Panda, Puravi, Nguyen, Dat Tuan, Leong, Nancy C.P., Sangermano, Riccardo, Patankar, Sohil G., Abdel-Hamid, Mohamed S., AlAbdi, Lama, Safwat, Sylvia, Flannery, Kyle P., Dardas, Zain, Fatih, Jawid M., Murali, Chaya, Kannan, Varun, Lotze, Timothy E., Herman, Isabella, Ammouri, Farah, Rezich, Brianna, Efthymiou, Stephanie, Alavi, Shahryar, Murphy, David, Firoozfar, Zahra, Nasab, Mahya Ebrahimi, Bahreini, Amir, Ghasemi, Majid, Haridy, Nourelhoda A., Goldouzi, Hamid Reza, Eghbal, Fatemeh, Karimiani, Ehsan Ghayoor, Begtrup, Amber, Elloumi, Houda, Srinivasan, Varunvenkat M., Gowda, Vykuntaraju K., Du, Haowei, Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Marafi, Dana, Rodan, Lance, Isikay, Sedat, Rosenfeld, Jill A., Ramanathan, Subhadra, Staton, Michael, Oberg, Kerby C., Clark, Robin D., Wenman, Catharina, Loughlin, Sam, Saad, Ramy, Ashraf, Tazeen, Male, Alison, Tadros, Shereen, Boostani, Reza, Abdel-Salam, Ghada M.H., Zaki, Maha, Mardi, Ali, Hashemi-Gorji, Farzad, Abdalla, Ebtesam, Manzini, M. Chiara, Pehlivan, Davut, Posey, Jennifer E., Gibbs, Richard A., Houlden, Henry, Alkuraya, Fowzan S., Bujakowska, Kinga, Maroofian, Reza, Lupski, James R., and Nguyen, Long N.
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- 2024
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19. Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders
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Cali, Elisa, Quirin, Tania, Rocca, Clarissa, Efthymiou, Stephanie, Riva, Antonella, Marafi, Dana, Zaki, Maha S., Suri, Mohnish, Dominguez, Roberto, Elbendary, Hasnaa M., Alavi, Shahryar, Abdel-Hamid, Mohamed S., Morsy, Heba, Mau-Them, Frederic Tran, Nizon, Mathilde, Tesner, Pavel, Ryba, Lukáš, Zafar, Faisal, Rana, Nuzhat, Saadi, Nebal W., Firoozfar, Zahra, Gencpinar, Pinar, Unay, Bulent, Ustun, Canan, Bruel, Ange-Line, Coubes, Christine, Stefanich, Jennifer, Sezer, Ozlem, Agolini, Emanuele, Novelli, Antonio, Vasco, Gessica, Lettori, Donatella, Milh, Mathieu, Villard, Laurent, Zeidler, Shimriet, Opperman, Henry, Strehlow, Vincent, Issa, Mahmoud Y., El Khassab, Hebatallah, Chand, Prem, Ibrahim, Shahnaz, Nejad-Rashidi, Ali, Miryounesi, Mohammad, Larki, Pegah, Morrison, Jennifer, Cristian, Ingrid, Thiffault, Isabelle, Bertsch, Nicole L., Noh, Grace J., Pappas, John, Moran, Ellen, Marinakis, Nikolaos M., Traeger-Synodinos, Joanne, Hosseini, Susan, Abbaszadegan, Mohammad Reza, Caumes, Roseline, Vissers, Lisenka E.L.M., Neshatdoust, Maedeh, Montazer, Mostafa Zohour, El Fahime, Elmostafa, Canavati, Christin, Kamal, Lara, Kanaan, Moien, Askander, Omar, Voinova, Victoria, Levchenko, Olga, Haider, Shahzhad, Halbach, Sara S., Maia, Elias Rayana, Mansoor, Salehi, Vivek, Jain, Tawde, Sanjukta, Challa, Viveka Santhosh R., Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Victor, Lucas Alves, Pinero-Banos, Benito, Hague, Jennifer, Ei-Awady, Heba Ahmed, Maria de Miranda Henriques-Souza, Adelia, Cheema, Huma Arshad, Anjum, Muhammad Nadeem, Idkaidak, Sara, Alqarajeh, Firas, Atawneh, Osama, Mor-Shaked, Hagar, Harel, Tamar, Zifarelli, Giovanni, Bauer, Peter, Kok, Fernando, Kitajima, Joao Paulo, Monteiro, Fabiola, Josahkian, Juliana, Lesca, Gaetan, Chatron, Nicolas, Ville, Dorothe, Murphy, David, Neul, Jeffrey L., Mullegama, Sureni V., Begtrup, Amber, Herman, Isabella, Mitani, Tadahiro, Posey, Jennifer E., Tay, Chee Geap, Javed, Iram, Carr, Lucinda, Kanani, Farah, Beecroft, Fiona, Hane, Lee, Abdelkreem, Elsayed, Macek, Milan, Bispo, Luciana, Elmaksoud, Marwa Abd, Hashemi-Gorji, Farzad, Pehlivan, Davut, Amor, David J., Jamra, Rami Abou, Chung, Wendy K., Ghayoor, Eshan Karimiani, Campeau, Philippe, Alkuraya, Fowzan S., Pagnamenta, Alistair T., Gleeson, Joseph, Lupski, James R., Striano, Pasquale, Moreno-De-Luca, Andres, Lafontaine, Denis L.J., Houlden, Henry, and Maroofian, Reza
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- 2024
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20. The impact of the Turkish population variome on the genomic architecture of rare disease traits
- Author
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Coban-Akdemir, Zeynep, Song, Xiaofei, Ceballos, Francisco C., Pehlivan, Davut, Karaca, Ender, Bayram, Yavuz, Mitani, Tadahiro, Gambin, Tomasz, Bozkurt-Yozgatli, Tugce, Jhangiani, Shalini N., Muzny, Donna M., Lewis, Richard A., Liu, Pengfei, Boerwinkle, Eric, Hamosh, Ada, Gibbs, Richard A., Sutton, V. Reid, Sobreira, Nara, Carvalho, Claudia M.B., Shaw, Chad A., Posey, Jennifer E., Valle, David, and Lupski, James R.
- Published
- 2024
- Full Text
- View/download PDF
21. Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency
- Author
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Alinger, Joshua B., Mace, Emily M., Porter, Justin.R., Mah-Som, Annelise Y., Daugherty, Allyssa L., Li, Stephanie, Throm, Allison A., Pingel, Jeanette T., Saucier, Nermina, Yao, Albert, Chinn, Ivan K., Lupski, James R., Ehlayel, Mohammad, Keller, Michael, Bowman, Greg R., Cooper, Megan A., Orange, Jordan S., and French, Anthony R.
- Published
- 2024
- Full Text
- View/download PDF
22. SNV/indel hypermutator phenotype in biallelic RAD51C variant: Fanconi anemia
- Author
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Zemet, Roni, Du, Haowei, Gambin, Tomasz, Lupski, James R., Liu, Pengfei, and Stankiewicz, Paweł
- Published
- 2023
- Full Text
- View/download PDF
23. FOXI3 pathogenic variants cause one form of craniofacial microsomia
- Author
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Mao, Ke, Borel, Christelle, Ansar, Muhammad, Jolly, Angad, Makrythanasis, Periklis, Froehlich, Christine, Iwaszkiewicz, Justyna, Wang, Bingqing, Xu, Xiaopeng, Li, Qiang, Blanc, Xavier, Zhu, Hao, Chen, Qi, Jin, Fujun, Ankamreddy, Harinarayana, Singh, Sunita, Zhang, Hongyuan, Wang, Xiaogang, Chen, Peiwei, Ranza, Emmanuelle, Paracha, Sohail Aziz, Shah, Syed Fahim, Guida, Valentina, Piceci-Sparascio, Francesca, Melis, Daniela, Dallapiccola, Bruno, Digilio, Maria Cristina, Novelli, Antonio, Magliozzi, Monia, Fadda, Maria Teresa, Streff, Haley, Machol, Keren, Lewis, Richard A., Zoete, Vincent, Squeo, Gabriella Maria, Prontera, Paolo, Mancano, Giorgia, Gori, Giulia, Mariani, Milena, Selicorni, Angelo, Psoni, Stavroula, Fryssira, Helen, Douzgou, Sofia, Marlin, Sandrine, Biskup, Saskia, De Luca, Alessandro, Merla, Giuseppe, Zhao, Shouqin, Cox, Timothy C., Groves, Andrew K., Lupski, James R., Zhang, Qingguo, Zhang, Yong-Biao, and Antonarakis, Stylianos E.
- Published
- 2023
- Full Text
- View/download PDF
24. Excess folic acid intake increases DNA de novo point mutations
- Author
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Cao, Xuanye, Xu, Jianfeng, Lin, Ying L., Cabrera, Robert M., Chen, Qiuying, Zhang, Chaofan, Steele, John W., Han, Xiao, Gross, Steven S., Wlodarczyk, Bogdan J., Lupski, James R., Li, Wei, Wang, Hongyan, Finnell, Richard H., and Lei, Yunping
- Published
- 2023
- Full Text
- View/download PDF
25. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients
- Author
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Le Coz, Carole, Nguyen, David N, Su, Chun, Nolan, Brian E, Albrecht, Amanda V, Xhani, Suela, Sun, Di, Demaree, Benjamin, Pillarisetti, Piyush, Khanna, Caroline, Wright, Francis, Chen, Peixin Amy, Yoon, Samuel, Stiegler, Amy L, Maurer, Kelly, Garifallou, James P, Rymaszewski, Amy, Kroft, Steven H, Olson, Timothy S, Seif, Alix E, Wertheim, Gerald, Grant, Struan FA, Vo, Linda T, Puck, Jennifer M, Sullivan, Kathleen E, Routes, John M, Zakharova, Viktoria, Shcherbina, Anna, Mukhina, Anna, Rudy, Natasha L, Hurst, Anna CE, Atkinson, T Prescott, Boggon, Titus J, Hakonarson, Hakon, Abate, Adam R, Hajjar, Joud, Nicholas, Sarah K, Lupski, James R, Verbsky, James, Chinn, Ivan K, Gonzalez, Michael V, Wells, Andrew D, Marson, Alex, Poon, Gregory MK, and Romberg, Neil
- Subjects
Human Genome ,Clinical Research ,Stem Cell Research - Nonembryonic - Human ,Biotechnology ,Regenerative Medicine ,Genetics ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,Hematology ,Adolescent ,Adult ,Agammaglobulinemia ,B-Lymphocytes ,Cell Differentiation ,Cell Line ,Child ,Child ,Preschool ,Chromatin ,Dendritic Cells ,Female ,Gene Expression Regulation ,Developmental ,HEK293 Cells ,Hematopoiesis ,Hematopoietic Stem Cells ,Humans ,Infant ,Lymphopoiesis ,Male ,Mutation ,Precursor Cells ,B-Lymphoid ,Proto-Oncogene Proteins ,Stem Cells ,Trans-Activators ,Young Adult ,Medical and Health Sciences ,Immunology - Abstract
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
- Published
- 2021
26. Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder
- Author
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Hengel, Holger, Hannan, Shabab B, Dyack, Sarah, MacKay, Sara B, Schatz, Ulrich, Fleger, Martin, Kurringer, Andreas, Balousha, Ghassan, Ghanim, Zaid, Alkuraya, Fowzan S, Alzaidan, Hamad, Alsaif, Hessa S, Mitani, Tadahiro, Bozdogan, Sevcan, Pehlivan, Davut, Lupski, James R, Gleeson, Joseph J, Dehghani, Mohammadreza, Mehrjardi, Mohammad YV, Sherr, Elliott H, Parks, Kendall C, Argilli, Emanuela, Begtrup, Amber, Galehdari, Hamid, Balousha, Osama, Shariati, Gholamreza, Mazaheri, Neda, Malamiri, Reza A, Pagnamenta, Alistair T, Kingston, Helen, Banka, Siddharth, Jackson, Adam, Osmond, Mathew, Consortium, Care4Rare Canada, Consortium, Genomics England Research, Rieß, Angelika, Haack, Tobias B, Nägele, Thomas, Schuster, Stefanie, Hauser, Stefan, Admard, Jakob, Casadei, Nicolas, Velic, Ana, Macek, Boris, Ossowski, Stephan, Houlden, Henry, Maroofian, Reza, and Schöls, Ludger
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Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Genetics ,Human Genome ,Brain Disorders ,Congenital Structural Anomalies ,Pediatric ,Aetiology ,2.1 Biological and endogenous factors ,Adolescent ,Adult ,Animals ,Cell Movement ,Child ,Child ,Preschool ,Drosophila ,Female ,Fibroblasts ,Humans ,Infant ,Loss of Function Mutation ,Loss of Heterozygosity ,Male ,Mice ,Mice ,Knockout ,Neoplasm Proteins ,Neurodevelopmental Disorders ,Pedigree ,Proteome ,Young Adult ,Care4Rare Canada Consortium ,Genomics England Research Consortium ,BCAS3 ,UAS-Gal4 ,fibroblasts ,global developmental delay ,microcephaly ,neurodevelopmental disorder ,proteomics ,pyramidal tract involvement ,thin corpus callosum ,transcriptomics ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.
- Published
- 2021
27. PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects
- Author
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Petit, Florence, Longoni, Mauro, Wells, Julie, Maser, Richard S., Bogenschutz, Eric L., Dysart, Matthew J., Contreras, Hannah T.M., Frénois, Frederic, Pober, Barbara R., Clark, Robin D., Giampietro, Philip F., Ropers, Hilger H., Hu, Hao, Loscertales, Maria, Wagner, Richard, Ai, Xingbin, Brand, Harrison, Jourdain, Anne-Sophie, Delrue, Marie-Ange, Gilbert-Dussardier, Brigitte, Devisme, Louise, Keren, Boris, McCulley, David J., Qiao, Lu, Hernan, Rebecca, Wynn, Julia, Scott, Tiana M., Calame, Daniel G., Coban-Akdemir, Zeynep, Hernandez, Patricia, Hernandez-Garcia, Andres, Yonath, Hagith, Lupski, James R., Shen, Yufeng, Chung, Wendy K., Scott, Daryl A., Bult, Carol J., Donahoe, Patricia K., and High, Frances A.
- Published
- 2023
- Full Text
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28. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease
- Author
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Calame, Daniel G., Guo, Tianyu, Wang, Chen, Garrett, Lillian, Jolly, Angad, Dawood, Moez, Kurolap, Alina, Henig, Noa Zunz, Fatih, Jawid M., Herman, Isabella, Du, Haowei, Mitani, Tadahiro, Becker, Lore, Rathkolb, Birgit, Gerlini, Raffaele, Seisenberger, Claudia, Marschall, Susan, Hunter, Jill V., Gerard, Amanda, Heidlebaugh, Alexis, Challman, Thomas, Spillmann, Rebecca C., Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Lalani, Seema, Liu, Lingxiao, Revah-Politi, Anya, Iglesias, Alejandro, Guzman, Edwin, Baugh, Evan, Boddaert, Nathalie, Rondeau, Sophie, Ormieres, Clothide, Barcia, Giulia, Tan, Queenie K.G., Thiffault, Isabelle, Pastinen, Tomi, Sheikh, Kazim, Biliciler, Suur, Mei, Davide, Melani, Federico, Shashi, Vandana, Yaron, Yuval, Steele, Mary, Wakeling, Emma, Østergaard, Elsebet, Nazaryan-Petersen, Lusine, Millan, Francisca, Santiago-Sim, Teresa, Thevenon, Julien, Bruel, Ange-Line, Thauvin-Robinet, Christel, Popp, Denny, Platzer, Konrad, Gawlinski, Pawel, Wiszniewski, Wojciech, Marafi, Dana, Pehlivan, Davut, Posey, Jennifer E., Gibbs, Richard A., Gailus-Durner, Valerie, Guerrini, Renzo, Fuchs, Helmut, Hrabě de Angelis, Martin, Hölter, Sabine M., Cheung, Hoi-Hung, Gu, Shen, and Lupski, James R.
- Published
- 2023
- Full Text
- View/download PDF
29. Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome
- Author
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Jolly, Angad, Du, Haowei, Borel, Christelle, Chen, Na, Zhao, Sen, Grochowski, Christopher M., Duan, Ruizhi, Fatih, Jawid M., Dawood, Moez, Salvi, Sejal, Jhangiani, Shalini N., Muzny, Donna M., Koch, André, Rouskas, Konstantinos, Glentis, Stavros, Deligeoroglou, Efthymios, Bacopoulou, Flora, Wise, Carol A., Dietrich, Jennifer E., Van den Veyver, Ignatia B., Dimas, Antigone S., Brucker, Sara, Sutton, V. Reid, Gibbs, Richard A., Antonarakis, Stylianos E., Wu, Nan, Coban-Akdemir, Zeynep H., Zhu, Lan, Posey, Jennifer E., and Lupski, James R.
- Published
- 2023
- Full Text
- View/download PDF
30. The Deep Genome Project
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Lloyd, KC Kent, Adams, David J, Baynam, Gareth, Beaudet, Arthur L, Bosch, Fatima, Boycott, Kym M, Braun, Robert E, Caulfield, Mark, Cohn, Ronald, Dickinson, Mary E, Dobbie, Michael S, Flenniken, Ann M, Flicek, Paul, Galande, Sanjeev, Gao, Xiang, Grobler, Anne, Heaney, Jason D, Herault, Yann, de Angelis, Martin Hrabě, Lupski, James R, Lyonnet, Stanislas, Mallon, Ann-Marie, Mammano, Fabio, MacRae, Calum A, McInnes, Roderick, McKerlie, Colin, Meehan, Terrence F, Murray, Stephen A, Nutter, Lauryl MJ, Obata, Yuichi, Parkinson, Helen, Pepper, Michael S, Sedlacek, Radislav, Seong, Je Kyung, Shiroishi, Toshihiko, Smedley, Damian, Tocchini-Valentini, Glauco, Valle, David, Wang, Chi-Kuang Leo, Wells, Sara, White, Jacqueline, Wurst, Wolfgang, Xu, Ying, and Brown, Steve DM
- Subjects
Animals ,Genes ,Genome ,Humans ,Mice ,Mutation ,Phenotype ,Proteins ,Environmental Sciences ,Biological Sciences ,Information and Computing Sciences ,Bioinformatics - Published
- 2020
31. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders
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Ngo, Kathie J, Rexach, Jessica E, Lee, Hane, Petty, Lauren E, Perlman, Susan, Valera, Juliana M, Deignan, Joshua L, Mao, Yuanming, Aker, Mamdouh, Posey, Jennifer E, Jhangiani, Shalini N, Coban‐Akdemir, Zeynep H, Boerwinkle, Eric, Muzny, Donna, Nelson, Alexandra B, Hassin‐Baer, Sharon, Poke, Gemma, Neas, Katherine, Geschwind, Michael D, Grody, Wayne W, Gibbs, Richard, Geschwind, Daniel H, Lupski, James R, Below, Jennifer E, Nelson, Stanley F, and Fogel, Brent L
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Brain Disorders ,Human Genome ,Neurosciences ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Neurological ,Cerebellar Ataxia ,DNA Copy Number Variations ,Exome ,Genetic Association Studies ,Genetic Linkage ,Genetic Predisposition to Disease ,Humans ,Microsatellite Repeats ,Nervous System Diseases ,Exome Sequencing ,ataxia ,cerebellar ataxia ,cerebellum ,diagnostic testing ,exome ,gait disorders ,genetics ,genomics ,neurogenetics ,spastic paraparesis ,spastic paraplegia ,spinocerebellar ataxia ,Clinical Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.
- Published
- 2020
32. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability
- Author
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Bogaert, Elke, Garde, Aurore, Gautier, Thierry, Rooney, Kathleen, Duffourd, Yannis, LeBlanc, Pontus, van Reempts, Emma, Tran Mau-Them, Frederic, Wentzensen, Ingrid M., Au, Kit Sing, Richardson, Kate, Northrup, Hope, Gatinois, Vincent, Geneviève, David, Louie, Raymond J., Lyons, Michael J., Laulund, Lone Walentin, Brasch-Andersen, Charlotte, Maxel Juul, Trine, El It, Fatima, Marle, Nathalie, Callier, Patrick, Relator, Raissa, Haghshenas, Sadegheh, McConkey, Haley, Kerkhof, Jennifer, Cesario, Claudia, Novelli, Antonio, Brunetti-Pierri, Nicola, Pinelli, Michele, Pennamen, Perrine, Naudion, Sophie, Legendre, Marine, Courdier, Cécile, Trimouille, Aurelien, Fenzy, Martine Doco, Pais, Lynn, Yeung, Alison, Nugent, Kimberly, Roeder, Elizabeth R., Mitani, Tadahiro, Posey, Jennifer E., Calame, Daniel, Yonath, Hagith, Rosenfeld, Jill A., Musante, Luciana, Faletra, Flavio, Montanari, Francesca, Sartor, Giovanna, Vancini, Alessandra, Seri, Marco, Besmond, Claude, Poirier, Karine, Hubert, Laurence, Hemelsoet, Dimitri, Munnich, Arnold, Lupski, James R., Philippe, Christophe, Thauvin-Robinet, Christel, Faivre, Laurence, Sadikovic, Bekim, Govin, Jérôme, Dermaut, Bart, and Vitobello, Antonio
- Published
- 2023
- Full Text
- View/download PDF
33. Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly
- Author
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Serey-Gaut, Margaux, Cortes, Marisol, Makrythanasis, Periklis, Suri, Mohnish, Taylor, Alexander M.R., Sullivan, Jennifer A., Asleh, Ayat N., Mitra, Jaba, Dar, Mohamad A., McNamara, Amy, Shashi, Vandana, Dugan, Sarah, Song, Xiaofei, Rosenfeld, Jill A., Cabrol, Christelle, Iwaszkiewicz, Justyna, Zoete, Vincent, Pehlivan, Davut, Akdemir, Zeynep Coban, Roeder, Elizabeth R., Littlejohn, Rebecca Okashah, Dibra, Harpreet K., Byrd, Philip J., Stewart, Grant S., Geckinli, Bilgen B., Posey, Jennifer, Westman, Rachel, Jungbluth, Chelsy, Eason, Jacqueline, Sachdev, Rani, Evans, Carey-Anne, Lemire, Gabrielle, VanNoy, Grace E., O’Donnell-Luria, Anne, Mau-Them, Frédéric Tran, Juven, Aurélien, Piard, Juliette, Nixon, Cheng Yee, Zhu, Ying, Ha, Taekjip, Buckley, Michael F., Thauvin, Christel, Essien Umanah, George K., Van Maldergem, Lionel, Lupski, James R., Roscioli, Tony, Dawson, Valina L., Dawson, Ted M., and Antonarakis, Stylianos E.
- Published
- 2023
- Full Text
- View/download PDF
34. Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome
- Author
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Faqeih, Eissa A., Alghamdi, Malak Ali, Almahroos, Marwa A., Alharby, Essa, Almuntashri, Makki, Alshangiti, Amnah M., Clément, Prouteau, Calame, Daniel G., Qebibo, Leila, Burglen, Lydie, Doco-Fenzy, Martine, Mastrangelo, Mario, Torella, Annalaura, Manti, Filippo, Nigro, Vincenzo, Alban, Ziegler, Alharbi, Ghadeer Saleh, Hashmi, Jamil Amjad, Alraddadi, Rawya, Alamri, Razan, Mitani, Tadahiro, Magalie, Barth, Coban-Akdemir, Zeynep, Geckinli, Bilgen Bilge, Pehlivan, Davut, Romito, Antonio, Karageorgou, Vasiliki, Martini, Javier, Colin, Estelle, Bonneau, Dominique, Bertoli-Avella, Aida, Lupski, James R., Pastore, Annalisa, Peake, Roy W.A., Dallol, Ashraf, Alfadhel, Majid, and Almontashiri, Naif A.M.
- Published
- 2023
- Full Text
- View/download PDF
35. Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly
- Author
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Link, Nichole, Chung, Hyunglok, Jolly, Angad, Withers, Marjorie, Tepe, Burak, Arenkiel, Benjamin R, Shah, Priya S, Krogan, Nevan J, Aydin, Hatip, Geckinli, Bilgen B, Tos, Tulay, Isikay, Sedat, Tuysuz, Beyhan, Mochida, Ganesh H, Thomas, Ajay X, Clark, Robin D, Mirzaa, Ghayda M, Lupski, James R, and Bellen, Hugo J
- Subjects
Genetics ,Rare Diseases ,Pediatric ,Stem Cell Research ,Congenital Structural Anomalies ,Neurological ,Good Health and Well Being ,Animals ,Asymmetric Cell Division ,Cell Division ,Cell Polarity ,Drosophila melanogaster ,Humans ,Membrane Proteins ,Microcephaly ,Mutation ,Neural Stem Cells ,Neurons ,Nuclear Proteins ,Zika Virus ,Ballchen ,Bazooka ,L(2)gl ,MCPH16 ,Miranda ,NS4A ,VRK1 ,aPKC ,brain development ,congenital infection ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division.
- Published
- 2019
36. A large CRISPR-induced bystander mutation causes immune dysregulation.
- Author
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Simeonov, Dimitre R, Brandt, Alexander J, Chan, Alice Y, Cortez, Jessica T, Li, Zhongmei, Woo, Jonathan M, Lee, Youjin, Carvalho, Claudia MB, Indart, Alyssa C, Roth, Theodore L, Zou, James, May, Andrew P, Lupski, James R, Anderson, Mark S, Buaas, F William, Rokhsar, Daniel S, and Marson, Alexander
- Subjects
T-Lymphocytes ,Cells ,Cultured ,Animals ,Mice ,Inbred NOD ,DNA Damage ,DNA Repair ,Gene Expression Regulation ,Gene Duplication ,Base Sequence ,Mutation ,T-Lymphocytes ,Regulatory ,Interleukin-2 Receptor alpha Subunit ,CRISPR-Cas Systems ,Gene Editing ,Cells ,Cultured ,Mice ,Inbred NOD ,Regulatory - Abstract
A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360 bp intronic enhancer, here we discovered a founder line that had marked immune dysregulation caused by a 24 kb tandem duplication of the sequence adjacent to the on-target deletion. Our results suggest unintended repair of on-target genomic cuts can cause pathogenic "bystander" mutations that escape detection by routine targeted genotyping assays.
- Published
- 2019
37. TLR7 gain-of-function genetic variation causes human lupus
- Author
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Brown, Grant J., Cañete, Pablo F., Wang, Hao, Medhavy, Arti, Bones, Josiah, Roco, Jonathan A., He, Yuke, Qin, Yuting, Cappello, Jean, Ellyard, Julia I., Bassett, Katharine, Shen, Qian, Burgio, Gaetan, Zhang, Yaoyuan, Turnbull, Cynthia, Meng, Xiangpeng, Wu, Phil, Cho, Eun, Miosge, Lisa A., Andrews, T. Daniel, Field, Matt A., Tvorogov, Denis, Lopez, Angel F., Babon, Jeffrey J., López, Cristina Aparicio, Gónzalez-Murillo, África, Garulo, Daniel Clemente, Pascual, Virginia, Levy, Tess, Mallack, Eric J., Calame, Daniel G., Lotze, Timothy, Lupski, James R., Ding, Huihua, Ullah, Tomalika R., Walters, Giles D., Koina, Mark E., Cook, Matthew C., Shen, Nan, de Lucas Collantes, Carmen, Corry, Ben, Gantier, Michael P., Athanasopoulos, Vicki, and Vinuesa, Carola G.
- Published
- 2022
- Full Text
- View/download PDF
38. Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract
- Author
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Münch, Johannes, Engesser, Marie, Schönauer, Ria, Hamm, J. Austin, Hartig, Christin, Hantmann, Elena, Akay, Gulsen, Pehlivan, Davut, Mitani, Tadahiro, Coban Akdemir, Zeynep, Tüysüz, Beyhan, Shirakawa, Toshihiko, Dateki, Sumito, Claus, Laura R., van Eerde, Albertien M., Smol, Thomas, Devisme, Louise, Franquet, Hélène, Attié-Bitach, Tania, Wagner, Timo, Bergmann, Carsten, Höhn, Anne Kathrin, Shril, Shirlee, Pollack, Ari, Wenger, Tara, Scott, Abbey A., Paolucci, Sarah, Buchan, Jillian, Gabriel, George C., Posey, Jennifer E., Lupski, James R., Petit, Florence, McCarthy, Andrew A., Pazour, Gregory J., Lo, Cecilia W., Popp, Bernt, and Halbritter, Jan
- Published
- 2022
- Full Text
- View/download PDF
39. Xq26.3 duplication in a boy with motor delay and low muscle tone refines the X-linked acrogigantism genetic locus
- Author
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Trivellin, Giampaolo, Sharwood, Erin, Hijazi, Hadia, Carvalho, Claudia MB, Yuan, Bo, Tatton-Brown, Katrina, Coman, David, Lupski, James R, Cotterill, Andrew M, Lodish, Maya B, and Stratakis, Constantine A
- Subjects
Genetics ,Human Genome ,Clinical Research - Abstract
We describe a 4-year-old boy with developmental delay who was found to carry by clinical grade (CG) molecular cytogenetics (MCs) a chromosome Xq26 microduplication. The report prompted a referral of the patient for possible X-linked acrogigantism (X-LAG), a well-defined condition (MIM300942) due to chromosomal microduplication of a nearby region. The patient was evaluated clinically and investigated for endocrine abnormalities related to X-LAG and not only did he not have acrogigantism, but his growth parameters and other hormones were all normal. We then performed high definition MCs and the duplication copy number variant (CNV) was confirmed to precisely map outside the X-LAG critical region and definitely did not harbor the X-LAG candidate gene, GPR101. The patient's phenotype resembled that of other patients with Xq26 CNVs. The case is instructive for the need for high definition MCs when CG MCs' results are inconsistent with the patient's phenotype. It is also useful for further supporting the contention that GPR101 is the gene responsible for X-LAG.
- Published
- 2018
40. Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.
- Author
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Li, Lin, Jiao, Xiaodong, D'Atri, Ilaria, Ono, Fumihito, Nelson, Ralph, Chan, Chi-Chao, Nakaya, Naoki, Ma, Zhiwei, Ma, Yan, Cai, Xiaoying, Zhang, Longhua, Lin, Siying, Hameed, Abdul, Chioza, Barry A, Hardy, Holly, Arno, Gavin, Hull, Sarah, Khan, Muhammad Imran, Fasham, James, Harlalka, Gaurav V, Michaelides, Michel, Moore, Anthony T, Coban Akdemir, Zeynep Hande, Jhangiani, Shalini, Lupski, James R, Cremers, Frans PM, Qamar, Raheel, Salman, Ahmed, Chilton, John, Self, Jay, Ayyagari, Radha, Kabir, Firoz, Naeem, Muhammad Asif, Ali, Muhammad, Akram, Javed, Sieving, Paul A, Riazuddin, Sheikh, Baple, Emma L, Riazuddin, S Amer, Crosby, Andrew H, and Hejtmancik, J Fielding
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Retina ,Cell Line ,Cytoplasm ,Animals ,Mice ,Knockout ,Zebrafish ,Humans ,Mice ,Retinitis Pigmentosa ,Chloride Channels ,Eye Proteins ,Homozygote ,Mutation ,Missense ,Asian Continental Ancestry Group ,Pakistan ,Retinal Rod Photoreceptor Cells ,Retinal Cone Photoreceptor Cells ,HEK293 Cells ,Neurodegenerative ,Eye Disease and Disorders of Vision ,Genetics ,Neurosciences ,Rare Diseases ,2.1 Biological and endogenous factors ,Eye ,Developmental Biology - Abstract
We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.
- Published
- 2018
41. Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders
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Zhao, Sen, Zhang, Yuanqiang, Hallgrimsdottir, Sigrun, Zuo, Yuzhi, Li, Xiaoxin, Batkovskyte, Dominyka, Liu, Sen, Lindelöf, Hillevi, Wang, Shengru, Hammarsjö, Anna, Yang, Yang, Ye, Yongyu, Wang, Lianlei, Yan, Zihui, Lin, Jiachen, Yu, Chenxi, Chen, Zefu, Niu, Yuchen, Wang, Huizi, Zhao, Zhi, Liu, Pengfei, Qiu, Guixing, Posey, Jennifer E., Wu, Zhihong, Lupski, James R., Micule, Ieva, Anderlid, Britt-Marie, Voss, Ulrika, Sulander, Dennis, Kuchinskaya, Ekaterina, Nordgren, Ann, Nilsson, Ola, Zhang, Terry Jianguo, Grigelioniene, Giedre, and Wu, Nan
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- 2022
- Full Text
- View/download PDF
42. Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits
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Yuan, Bo, Schulze, Katharina V., Assia Batzir, Nurit, Sinson, Jefferson, Dai, Hongzheng, Zhu, Wenmiao, Bocanegra, Francia, Fong, Chin-To, Holder, Jimmy, Nguyen, Joanne, Schaaf, Christian P., Yang, Yaping, Bi, Weimin, Eng, Christine, Shaw, Chad, Lupski, James R., and Liu, Pengfei
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- 2022
- Full Text
- View/download PDF
43. The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation
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Du, Haowei, Jolly, Angad, Grochowski, Christopher M., Yuan, Bo, Dawood, Moez, Jhangiani, Shalini N., Li, He, Muzny, Donna, Fatih, Jawid M., Coban-Akdemir, Zeynep, Carlin, Mary Esther, Scheuerle, Angela E., Witzl, Karin, Posey, Jennifer E., Pendleton, Matthew, Harrington, Eoghan, Juul, Sissel, Hastings, P. J., Bi, Weimin, Gibbs, Richard A., Sedlazeck, Fritz J., Lupski, James R., Carvalho, Claudia M. B., and Liu, Pengfei
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- 2022
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- View/download PDF
44. Exome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension
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Copeland, Ian, primary, Wonkam-Tingang, Edmond, additional, Gupta-Malhotra, Monesha, additional, Hashmi, S. Shahrukh, additional, Han, Yixing, additional, Jajoo, Aarti, additional, Hall, Nancy J., additional, Hernandez, Paula P., additional, Lie, Natasha, additional, Liu, Dan, additional, Xu, Jun, additional, Rosenfeld, Jill, additional, Haldipur, Aparna, additional, Desire, Zelene, additional, Coban-Akdemir, Zeynep H., additional, Scott, Daryl A., additional, Li, Qing, additional, Chao, Hsiao-Tuan, additional, Zaske, Ana M., additional, Lupski, James R., additional, Milewicz, Dianna M., additional, Shete, Sanjay, additional, Posey, Jennifer E., additional, and Hanchard, Neil A., additional
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- 2024
- Full Text
- View/download PDF
45. Defining and Reducing Variant Classification Disparities
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Dawood, Moez, primary, Fayer, Shawn, additional, Pendyala, Sriram, additional, Post, Mason, additional, Kalra, Divya, additional, Patterson, Karynne, additional, Venner, Eric, additional, Muffley, Lara A., additional, Fowler, Douglas M., additional, Rubin, Alan F., additional, Posey, Jennifer E., additional, Plon, Sharon E., additional, Lupski, James R., additional, Gibbs, Richard A., additional, Starita, Lea M., additional, Robles-Espinoza, Carla Daniela, additional, Coyote-Maestas, Willow, additional, and Gallego Romero, Irene, additional
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- 2024
- Full Text
- View/download PDF
46. AHDC1 missense mutations in Xia-Gibbs syndrome
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Khayat, Michael M., Hu, Jianhong, Jiang, Yunyun, Li, He, Chander, Varuna, Dawood, Moez, Hansen, Adam W., Li, Shoudong, Friedman, Jennifer, Cross, Laura, Bijlsma, Emilia K., Ruivenkamp, Claudia A.L., Sansbury, Francis H., Innis, Jeffrey W., Omark O’Shea, Jessica, Meng, Qingchang, Rosenfeld, Jill A., McWalter, Kirsty, Wangler, Michael F., Lupski, James R., Posey, Jennifer E., Murdock, David, and Gibbs, Richard A.
- Published
- 2021
- Full Text
- View/download PDF
47. Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity
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Thomas, Quentin, Gautier, Thierry, Marafi, Dana, Besnard, Thomas, Willems, Marjolaine, Moutton, Sébastien, Isidor, Bertand, Cogné, Benjamin, Conrad, Solène, Tenconi, Romano, Iascone, Maria, Sorlin, Arthur, Masurel, Alice, Dabir, Tabib, Jackson, Adam, Banka, Siddharth, Delanne, Julian, Lupski, James R., Saadi, Nebal Waill, Alkuraya, Fowzan S., Zahrani, Fatema Al, Agrawal, Pankaj B., England, Eleina, Madden, Jill A., Posey, Jennifer E., Burglen, Lydie, Rodriguez, Diana, Chevarin, Martin, Nguyen, Sylvie, Mau-Them, Frédéric Tran, Duffourd, Yannis, Garret, Philippine, Bruel, Ange-Line, Callier, Patrick, Marle, Nathalie, Denomme-Pichon, Anne-Sophie, Duplomb, Laurence, Philippe, Christophe, Thauvin-Robinet, Christel, Govin, Jérôme, Faivre, Laurence, and Vitobello, Antonio
- Published
- 2021
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- View/download PDF
48. Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
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Calame, Daniel G., Bakhtiari, Somayeh, Logan, Rachel, Coban-Akdemir, Zeynep, Du, Haowei, Mitani, Tadahiro, Fatih, Jawid M., Hunter, Jill V., Herman, Isabella, Pehlivan, Davut, Jhangiani, Shalini N., Person, Richard, Schnur, Rhonda E., Jin, Sheng Chih, Bilguvar, Kaya, Posey, Jennifer E., Koh, Sookyong, Firouzabadi, Saghar G., Alehabib, Elham, Tafakhori, Abbas, Esmkhani, Sahra, Gibbs, Richard A., Noureldeen, Mahmoud M., Zaki, Maha S., Marafi, Dana, Darvish, Hossein, Kruer, Michael C., and Lupski, James R.
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- 2021
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49. Prevalence of spinocerebellar ataxia 36 in a US population
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Valera, Juliana M, Diaz, Tatyana, Petty, Lauren E, Quintáns, Beatriz, Yáñez, Zuleima, Boerwinkle, Eric, Muzny, Donna, Akhmedov, Dmitry, Berdeaux, Rebecca, Sobrido, Maria J, Gibbs, Richard, Lupski, James R, Geschwind, Daniel H, Perlman, Susan, Below, Jennifer E, and Fogel, Brent L
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Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Clinical Research ,Rare Diseases ,Neurodegenerative ,Neurosciences ,Genetics ,Brain Disorders ,Neurological ,Clinical sciences - Abstract
ObjectiveTo assess the prevalence and clinical features of individuals affected by spinocerebellar ataxia 36 (SCA36) at a large tertiary referral center in the United States.MethodsA total of 577 patients with undiagnosed sporadic or familial cerebellar ataxia comprehensively evaluated at a tertiary referral ataxia center were molecularly evaluated for SCA36. Repeat primed PCR and fragment analysis were used to screen for the presence of a repeat expansion in the NOP56 gene.ResultsFragment analysis of triplet repeat primed PCR products identified a GGCCTG hexanucleotide repeat expansion in intron 1 of NOP56 in 4 index cases. These 4 SCA36-positive families comprised 2 distinct ethnic groups: white (European) (2) and Asian (Japanese [1] and Vietnamese [1]). Individuals affected by SCA36 exhibited typical clinical features with gait ataxia and age at onset ranging between 35 and 50 years. Patients also suffered from ataxic or spastic limbs, altered reflexes, abnormal ocular movement, and cognitive impairment.ConclusionsIn a US population, SCA36 was observed to be a rare disorder, accounting for 0.7% (4/577 index cases) of disease in a large undiagnosed ataxia cohort.
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- 2017
50. A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay
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Schoch, Kelly, Meng, Linyan, Szelinger, Szabolcs, Bearden, David R, Stray-Pedersen, Asbjorg, Busk, Oyvind L, Stong, Nicholas, Liston, Eriskay, Cohn, Ronald D, Scaglia, Fernando, Rosenfeld, Jill A, Tarpinian, Jennifer, Skraban, Cara M, Deardorff, Matthew A, Friedman, Jeremy N, Akdemir, Zeynep Coban, Walley, Nicole, Mikati, Mohamad A, Kranz, Peter G, Jasien, Joan, McConkie-Rosell, Allyn, McDonald, Marie, Wechsler, Stephanie Burns, Freemark, Michael, Kansagra, Sujay, Freedman, Sharon, Bali, Deeksha, Millan, Francisca, Bale, Sherri, Nelson, Stanley F, Lee, Hane, Dorrani, Naghmeh, Goldstein, David B, Xiao, Rui, Yang, Yaping, Posey, Jennifer E, Martinez-Agosto, Julian A, Lupski, James R, Wangler, Michael F, Shashi, Vandana, Grody, Wayne W, Strom, Samuel P, Vilain, Eric, Deignan, Joshua, Quintero-Rivera, Fabiola, Kantarci, Sibel, Mullegama, Sureni, Kang, Sung-Hae, Alejandro, Mercedes E, Bacino, Carlos A, Balasubramanyam, Ashok, Burrage, Lindsay C, Clark, Gary D, Craigen, William J, Dhar, Shweta U, Emrick, Lisa T, Graham, Brett H, Hanchard, Neil A, Jain, Mahim, Lalani, Seema R, Lee, Brendan H, Lewis, Richard A, Mashid, Azamian S, Moretti, Paolo M, Nicholas, Sarah K, Orange, Jordan S, Potocki, Lorraine, Scott, Daryl A, Tran, Alyssa A, Bellen, Hugo J, Yamamoto, Shinya, Eng, Christine M, Muzny, Donna M, Ward, Patricia A, Gropman, Andrea L, Jiang, Yong-hui, Pena, Loren DM, Spillmann, Rebecca C, Sullivan, Jennifer A, Walley, Nicole M, Beggs, Alan H, Briere, Lauren C, Cooper, Cynthia M, Donnell-Fink, Laurel A, Krieg, Elizabeth L, Krier, Joel B, and Lincoln, Sharyn A
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Neurosciences ,Pediatric ,Brain Disorders ,Neurodegenerative ,Epilepsy ,Intellectual and Developmental Disabilities (IDD) ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Alleles ,Amino Acid Sequence ,Brain ,Cataract ,Child ,Child ,Preschool ,Female ,Genetic Variation ,Genome-Wide Association Study ,Humans ,Infant ,Intellectual Disability ,Magnetic Resonance Imaging ,Male ,Microcephaly ,Mutation ,Missense ,Neoplasm Proteins ,Pedigree ,Phenotype ,Repressor Proteins ,Spasms ,Infantile ,UCLA Clinical Genomics Center ,Undiagnosed Diseases Network ,NACC1 ,cataracts ,developmental/intellectual disabilities ,epilepsy ,irritability ,microcephaly ,stereotypy ,whole-exome sequencing ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10-14). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.
- Published
- 2017
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