27 results on '"Zackai, Elaine"'
Search Results
2. The Dysmorphic Infant
- Author
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TAYLOR WILD, K., primary, SHEPPARD, SARAH E., additional, and ZACKAI, ELAINE H., additional
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- 2024
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3. Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome
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Strong, Alanna, March, Michael E., Cardinale, Christopher J., Liu, Yichuan, Battig, Mark R., Finoti, Livia Sertori, Matsuoka, Leticia S., Watson, Deborah, Sridhar, Sindura, Jarrett, James F., Cannon, India, Li, Dong, Bhoj, Elizabeth, Zackai, Elaine H., Rand, Elizabeth B., Wenger, Tara, Lerman, Bruce B., Shikany, Amy, Weaver, K. Nicole, and Hakonarson, Hakon
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- 2024
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4. Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling
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Boonsawat, Paranchai, Asadollahi, Reza, Niedrist, Dunja, Steindl, Katharina, Begemann, Anaïs, Joset, Pascal, Bhoj, Elizabeth J., Li, Dong, Zackai, Elaine, Vetro, Annalisa, Barba, Carmen, Guerrini, Renzo, Whalen, Sandra, Keren, Boris, Khan, Amjad, Jing, Duan, Palomares Bralo, María, Rikeros Orozco, Emi, Hao, Qin, Schlott Kristiansen, Britta, Zheng, Bixia, Donnelly, Deirdre, Clowes, Virginia, Zweier, Markus, Papik, Michael, Siegel, Gabriele, Sabatino, Valeria, Mocera, Martina, Horn, Anselm H.C., Sticht, Heinrich, and Rauch, Anita
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- 2024
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5. Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes
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Rots, Dmitrijs, Choufani, Sanaa, Faundes, Victor, Dingemans, Alexander J.M., Joss, Shelagh, Foulds, Nicola, Jones, Elizabeth A., Stewart, Sarah, Vasudevan, Pradeep, Dabir, Tabib, Park, Soo-Mi, Jewell, Rosalyn, Brown, Natasha, Pais, Lynn, Jacquemont, Sébastien, Jizi, Khadijé, Ravenswaaij-Arts, Conny M.A. van, Kroes, Hester Y., Stumpel, Constance T.R. M., Ockeloen, Charlotte W., Diets, Illja J., Nizon, Mathilde, Vincent, Marie, Cogné, Benjamin, Besnard, Thomas, Kambouris, Marios, Anderson, Emily, Zackai, Elaine H., McDougall, Carey, Donoghue, Sarah, O'Donnell-Luria, Anne, Valivullah, Zaheer, O'Leary, Melanie, Srivastava, Siddharth, Byers, Heather, Leslie, Nancy, Mazzola, Sarah, Tiller, George E., Vera, Moin, Shen, Joseph J., Boles, Richard, Jain, Vani, Brischoux-Boucher, Elise, Kinning, Esther, Simpson, Brittany N., Giltay, Jacques C., Harris, Jacqueline, Keren, Boris, Guimier, Anne, Marijon, Pierre, Vries, Bert B.A. de, Motter, Constance S., Mendelsohn, Bryce A., Coffino, Samantha, Gerkes, Erica H., Afenjar, Alexandra, Visconti, Paola, Bacchelli, Elena, Maestrini, Elena, Delahaye-Duriez, Andree, Gooch, Catherine, Hendriks, Yvonne, Adams, Hieab, Thauvin-Robinet, Christel, Josephi-Taylor, Sarah, Bertoli, Marta, Parker, Michael J., Rutten, Julie W., Caluseriu, Oana, Vernon, Hilary J., Kaziyev, Jonah, Zhu, Jia, Kremen, Jessica, Frazier, Zoe, Osika, Hailey, Breault, David, Nair, Sreelata, Lewis, Suzanne M.E., Ceroni, Fabiola, Viggiano, Marta, Posar, Annio, Brittain, Helen, Giovanna, Traficante, Giulia, Gori, Quteineh, Lina, Ha-Vinh Leuchter, Russia, Zonneveld-Huijssoon, Evelien, Mellado, Cecilia, Marey, Isabelle, Coudert, Alicia, Aracena Alvarez, Mariana Inés, Kennis, Milou G.P., Bouman, Arianne, Roifman, Maian, Amorós Rodríguez, María Inmaculada, Ortigoza-Escobar, Juan Dario, Vernimmen, Vivian, Sinnema, Margje, Pfundt, Rolph, Brunner, Han G., Vissers, Lisenka E.L.M., Kleefstra, Tjitske, Weksberg, Rosanna, and Banka, Siddharth
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- 2024
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6. Genomic Contributors to Esophageal Atresia and Tracheoesophageal Fistula: A 12 Year Retrospective Review
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Wild, K. Taylor, Conlin, Laura, Blair, Justin, Manfredi, Michael, Hamilton, Thomas E., Muir, Amanda, Zackai, Elaine H., Nace, Gary, Partridge, Emily A., Devine, Matthew, Reynolds, Tom, Rintoul, Natalie E., Hedrick, Holly L., Spinner, Nancy, and Krantz, Ian D.
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- 2024
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7. Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects
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Gaynor, J. William, primary, Moldenhauer, Julie S., additional, Zullo, Erin E., additional, Burnham, Nancy B., additional, Gerdes, Marsha, additional, Bernbaum, Judy C., additional, D’Agostino, Jo Ann, additional, Linn, Rebecca L., additional, Klepczynski, Brenna, additional, Randazzo, Isabel, additional, Gionet, Gabrielle, additional, Choi, Grace H., additional, Karaj, Antoneta, additional, Russell, William W., additional, Zackai, Elaine H., additional, Johnson, Mark P., additional, Gebb, Juliana S., additional, Soni, Shelly, additional, DeBari, Suzanne E., additional, Szwast, Anita L., additional, Ahrens-Nicklas, Rebecca C., additional, Drivas, Theodore G., additional, Jacobwitz, Marin, additional, Licht, Daniel J., additional, Vossough, Arastoo, additional, Nicolson, Susan C., additional, Spray, Thomas L., additional, Rychik, Jack, additional, and Putt, Mary E., additional
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- 2024
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8. Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age
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Freud, Lindsay R., Galloway, Stephanie, Crowley, T. Blaine, Moldenhauer, Julie, Swillen, Ann, Breckpot, Jeroen, Borrell, Antoni, Vora, Neeta L., Cuneo, Bettina, Hoffman, Hilary, Gilbert, Lisa, Nowakowska, Beata, Geremek, Maciej, Kutkowska-Kaźmierczak, Anna, Vermeesch, Joris R., Devriendt, Koen, Busa, Tiffany, Sigaudy, Sabine, Vigneswaran, Trisha, Simpson, John M., Dungan, Jeffrey, Gotteiner, Nina, Gloning, Karl-Philipp, Digilio, Maria Cristina, Unolt, Marta, Putotto, Carolina, Marino, Bruno, Repetto, Gabriela, Fadic, Magdalena, Garcia-Minaur, Sixto, Achón Buil, Ana, Thomas, Mary Ann, Fruitman, Deborah, Beecroft, Taylor, Hui, Pui Wah, Oskarsdottir, Solveig, Bradshaw, Rachael, Criebaum, Amanda, Norton, Mary E., Lee, Tiffany, Geiger, Miwa, Dunnington, Leslie, Isaac, Jacqueline, Wilkins-Haug, Louise, Hunter, Lindsey, Izzi, Claudia, Toscano, Marika, Ghi, Tullio, McGlynn, Julie, Romana Grati, Francesca, Emanuel, Beverly S., Gaiser, Kimberly, Gaynor, J. William, Goldmuntz, Elizabeth, McGinn, Daniel E., Schindewolf, Erica, Tran, Oanh, Zackai, Elaine H., Yan, Qi, Bassett, Anne S., Wapner, Ronald, and McDonald-McGinn, Donna M.
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- 2024
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9. Enlarged cavum septum pellucidum and small thymus as markers for 22q11.2 deletion syndrome
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Gaiser, Kimberly B., primary, Schindewolf, Erica M., additional, Conway, Laura J., additional, Coleman, Beverly G., additional, Oliver, Edward R., additional, Rychik, Jack R., additional, Debari, Suzanne E., additional, Mcdonald‐Mcginn, Donna M., additional, Zackai, Elaine H., additional, Moldenhauer, Julie S., additional, and Gebb, Juliana S., additional
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- 2024
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10. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features
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Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, Hakonarson, Hakon, Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, and Hakonarson, Hakon
- Abstract
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
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- 2024
11. Subdural Hemorrhage as an Early Presentation in a Case of Sotos Syndrome.
- Author
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Nomakuchi, Tomoki T., Alves, Cesar Augusto P., Beslow, Lauren A., Zarnow, Deborah, Goyal, Neera, Zackai, Elaine H., and Reynoso Santos, Francis Jeshira
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CHILD patients ,SUBARACHNOID space ,MEDICAL genetics ,CHILD abuse ,HEMORRHAGE - Abstract
Subdural hemorrhages (SDHs) in the pediatric population are associated with a high mortality and morbidity and may present in the context of abusive head trauma. Diagnostic investigations for such cases often include evaluation for rare genetic and metabolic disorders that can have associated SDH. Sotos syndrome is an overgrowth syndrome associated with macrocephaly and increased subarachnoid spaces and rarely with neurovascular complications. Here, we report two cases of Sotos syndrome, one with SDH during infancy who underwent repeated evaluation for suspected child abuse prior to the Sotos syndrome diagnosis and the other with enlarged extra-axial cerebrospinal fluid spaces, demonstrating a possible mechanism for SDH development in this setting. These cases suggest that some individuals with Sotos syndrome may be at elevated risk of developing SDH in infancy and that Sotos syndrome should be on the differential diagnosis during a medical genetics evaluation in cases of unexplained SDH, especially in the setting of macrocephaly. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions.
- Author
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Verscaj, Courtney P., Velez‐Bartolomei, Frances, Bodle, Ethan, Chan, Katie, Lyons, Michael J., Thorson, Willa, Tan, Wen‐Hann, Rodig, Nancy, Graham, John M., Peron, Angela, Quintero‐Rivera, Fabiola, Zackai, Elaine H., Thomas, Mary Ann, Stevens, Cathy A., Adam, Margaret P., Bird, Lynne M., Jones, Marilyn C., and Matalon, Dena R.
- Abstract
Objective: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized. Method: We reviewed pre‐ and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings. Results: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end‐stage renal disease during childhood or the follow‐up period. Conclusion: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management. Key points: What is already known about this topic? Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including renal abnormalities.Cystic renal changes, including cystic dysplasia, are the most commonly reported association postnatally. Hyperechogenic kidneys have been associated prenatally. What does this study add? This study broadens the spectrum of prenatal renal anomalies associated with 17q12 deletions.Despite prenatal onset of renal abnormalities, we demonstrate that individuals with 17q12 deletions displayed no progression to end‐stage renal disease during the postnatal follow‐up period. [ABSTRACT FROM AUTHOR]
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- 2024
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13. A case-control study of bleeding risk in children with 22q11.2 deletion syndrome undergoing cardiac surgery.
- Author
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Crowley, T. Blaine, Campbell, Ian, Arulselvan, Abinaya, Friedman, David, Zackai, Elaine H., Geoffrion, Tracy R., Witmer, Char, Gaynor, J. William, McDonald-McGinn, Donna M., and Lambert, Michele P.
- Subjects
DIGEORGE syndrome ,SURGICAL blood loss ,CHILDREN'S hospitals ,CONGENITAL heart disease ,PEDIATRIC surgery - Abstract
Previous research suggests that individuals with 22q11.2 deletion syndrome (DS) have an increased risk of bleeding following cardiac surgery. However, current guidelines for management of patients with 22q11.2DS do not provide specific recommendations for perioperative management. This study sought to identify specific risk factors for bleeding in this patient population. Examine the factors determining bleeding and transfusion requirements in patients with 22q11.2DS undergoing cardiac surgery. This was a single center review of patients who underwent cardiac surgery at the Children's Hospital of Philadelphia from 2000 to 2016. Data was extracted from the medical record. Frequency of bleeding events, laboratory values, and transfusion requirements were compared. We included 226 patients with 22q11.2DS and 506 controls. Bleeding events were identified in 13 patients with 22q11.2DS (5.8%) and 27 controls (5.3%). Platelet counts were lower among patients with 22q11.2DS than in control patients, but not statistically different comparing bleeding to not bleeding. Patients with 22q11.2DS received more transfusions (regardless of bleeding status). However, multivariate analysis showed only procedure type was associated with increased risk of bleeding (p = .012). The overall risk of bleeding when undergoing cardiac surgery is not different in patients with 22q11.2DS compared to non-deleted patients. Though platelet counts were lower in patients with 22q11.2DS, only procedure type was significantly associated with an increased risk of bleeding. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
14. Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA.
- Author
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Nriagu, Bede N., Williams, Lydia S., Brewer, Niambi, Surrey, Lea F., Srinivasan, Abhay S., Li, Dong, Britt, Allison, Treat, James, Crowley, T. Blaine, O'Connor, Nora, Ganguly, Arupa, Low, David, Queenan, Maria, Drivas, Theodore G., Zackai, Elaine H., Adams, Denise M., Hakonarson, Hakon, Snyder, Kristen M., and Sheppard, Sarah E.
- Abstract
Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co‐occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA—a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co‐occur in individuals with Turner syndrome. [ABSTRACT FROM AUTHOR]
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- 2024
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15. P386: Agenesis of olfactory apparatus due to intragenic deletion of SIN3A and MAN2C1 resulting in Witteveen-Kolk syndrome
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Donoghue, Sarah, Skraban, Cara, Squicciarini, Jake, Wang, Jing, Rippert, Alyssa, McDonald-McGinn, Donna, and Zackai, Elaine
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- 2024
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16. P217: Abnormalities of TBX1 result in broad overlapping features of 22q11.2 deletion syndrome
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McDonald-McGinn, Donna, Giunta, Victoria, Crowley, T. Blaine, McGinn, Daniel, Rockart, Lydia, Green, Audrey, Emanuel, Beverly, Smith, Rosemarie, Moran, Ellen, Geremek, Maciej, Zackai, Elaine, and Nowakowska, Beata
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- 2024
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17. 28 - Chromosome Disorders
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SENARATNE, T. NIROSHI, ZACKAI, ELAINE H., and SAITTA, SULAGNA C.
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- 2024
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18. 27 - The Dysmorphic Infant
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TAYLOR WILD, K., SHEPPARD, SARAH E., and ZACKAI, ELAINE H.
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- 2024
- Full Text
- View/download PDF
19. Contributors
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Abman, Steven H., Ali, Noorjahan, Allegaert, Karel, Anderson, Jamie E., Ansah, Deidra A., Arya, Bhawna, Askenazi, David, Aucott, Susan W., Back, Stephen A., Baer, Gerri R., Baldwin, H. Scott, Ballas, Jerasimos, Batra, Maneesh, Bayart, Cheryl, Bellus, Gary A., Benjamin, John T., Berry, Gerard T., Billimoria, Zeenia C., Binenbaum, Gil, Blessing, Matthew S., Boos, Markus D., Bosse, Brad, Bouchard, Maryse L., Brandling-Bennett, Heather A., Brown, Colleen, Brown, Erin G., Campbell, Katherine H., Carlberg, Katie, Carter, Brian S., Chabra, Shilpi, Chang, Irene J., Cheng, Edith Y., Chiang, Kai-wen, Christensen, Robert D., Chun, Terrence, Clyman, Ronald I., Cortezzo, Donna, Maria E., Cotten, C.M., Courtney, Sherry E., Davis, Jonathan M., de Alba Campomanes, Alejandra G., Dean, Benjamin, Dees, Ellen, De, Mauro, Sara B., Denne, Scott C., Deschmann, Emöke, Di Blasi, Carolina Cecilia, Di, Vall, Sara A., Doherty, Dan, Durand, David J., Dyess, Nicolle Fernández, Eichenwald, Eric C., Eitel, Kelsey B., Engen, Rachel M., Evans, Kelly N., Farmer, Diana L., Fay, Emily, Fechner, Patricia Y., Fleishman, Rachel, Fleiss, Bobbi, Flynn, Joseph, Jr., Flynn-O’Brien, Katherine T., Kyle Fulton, G., Gallagher, Renata C., Gauda, Estelle B., Christopher Golden, W., Gontasz, Michelle M., Estévez, Natasha González, Gospe, Sidney M., Jr., Gressens, Pierre, Gupta, Deepti, Hingorani, Sangeeta, Hinson, Ashley P., Hintz, Susan R., Alan Hodson, W., Hoppe, Kara K., Huang, Alyssa, Huang, Benjamin, Huen, Kathy, Huff, Katie A., Ionita, Cristian, Craig Jackson, J., Jackson, Jordan E., Jaksic, Tom, Javid, Patrick J., Johnson, Julia, Josephson, Cassandra D., Jungheim, Emily S., Juul, Sandra E., Kabbany, Mohammad Nasser, Karpen, Heidi, Keefe, Gregory, Keene, Jennifer C., Keiser, Amaris M., Keller, Roberta L., Kelly, Thomas F., Khorsand, Kate, Kim, Grace, Kinsella, John P., Komorowski, Allison S., Koves, Ildiko H., Lagatta, Joanne M., Lakshminrusimha, Satyan, Lam, Christina, Lantos, John D., Law, Janessa B., Lee, Su Yeon, Levy, Ofer, Lewis, David B., Lin, Philana Ling, Lorch, Scott A., Lucas, Tiffany L., Maheshwari, Akhil, Maltepe, Emin, Mandell, Erica, Manimtim, Winston M., Martin, Richard J., Mayock, Dennis E., Mc, Aleer, Irene, McQuillen, Patrick, Melvin, Ann J., Merguerian, Paul A., Merjaneh, Lina, Lawrence Merritt, J., Mezger, Valerie, Michaels, Marian G., Mietzsch, Ulrike, Miller, Steven P., Moore, Thomas R., Murray, Karen F., Nandi-Munshi, Debika, Natarajan, Niranjana, Ness, Kathryn D., Neu, Josef, Noori, Shahab, O’Shea, Thomas Michael, Jr., Oatts, Julius T., Paneth, Nigel, Parker, Thomas A., Patel, Ravi Mangal, Patel, Simran, Penn, Anna A., Pettker, Christian M., Peyvandi, Shabnam, Pihoker, Catherine, Plosa, Erin, Poindexter, Brenda, Posencheg, Michael A., Puia-Dumitrescu, Mihai, Cardona, Vilmaris Quiñones, Rice-Townsend, Samuel E., Riddle, Art, Robbins, Elizabeth, Rollins, Mark D., Rosen, Mark A., Rowe, Courtney K., Sahai, Inderneel, Saitta, Sulagna C., Salehi, Parisa, Sanchez, Pablo J., Sawyer, Taylor, Saxonhouse, Matthew A., Schroeder, Katherine M., Selewski, David T., Niroshi Senaratne, T., Seri, Istvan, Sharpe, Emily E., Sheppard, Sarah E., Shnorhavorian, Margarett, Sidbury, Robert, Simmons, La, Vone, Simmons, Rebecca A., Singh, Rachana, Sola-Visner, Martha C., Srinivasan, Lakshmi, Steflik, Heidi J., Steinhorn, Robin H., Stokes, Caleb, Stolp, Helen, Sucre, Jennifer, Sun, Angela, Taha, Dalal K., Tenney, Jessica, Thomas, Janet A., Tiller, George E., Torres, Benjamin A., Truog, William E., Upadhyay, Kirtikumar, Valentine, Gregory C., van den Anker, John N., Vohr, Betty, Wallen, Linda D., Wang, Peter (Zhan Tao), Warady, Bradley A., Ward, Robert M., Watchko, Jon F., Wehbi, Elias, Weitkamp, Joern-Hendrik, Werny, David, White, Klane K., Taylor Wild, K., Wiley, Susan, Willig, Laurel, Woodward, George A., Wright, Clyde J., Yonekawa, Karyn, Yu, Elizabeth, and Zackai, Elaine H.
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- 2024
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20. Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants
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Saeidian, Amir Hossein, March, Michael E., Youssefian, Leila, Watson, Deborah J., Bhandari, Esha, Wang, Xiang, Zhao, Xiaonan, Owen, Nichole Marie, Strong, Alanna, Harr, Margaret H., Aliazami, Farnoush, Ribeiro Carneiro, Thaise Nayane, Akbarzadeh, Mahdi, Kazemioula, Golnesa, Saeidian, Amir Hesam, Palizban, Fahimeh, Biglari, Sajjad, Coleman, David, Snyder, James, Wang, Fengxiang, Billings, Jonathan, Terek, Shannon, Mentch, Frank, Regan-Fendt, Kelly, Tsoi, Lam C., Dorrani, Naghmeh, Bhoj, Elizabeth, Zackai, Elaine, Vahidnezhad, Hassan, Gudjonsson, Johann, Cederbaum, Stephen D., Deignan, Joshua L., Glessner, Joseph, Grody, Wayne W., and Hakonarson, Hakon
- Abstract
Clinical next-generation sequencing is an effective approach for identifying pathogenic sequence variants that are medically actionable for participants and families but are not associated with the participant's primary diagnosis. These variants are called secondary findings (SFs). According to the literature, there is no report of the types and frequencies of SFs in a large pediatric cohort which includes substantial African-American participants. We sought to investigate the types (including American College of Medical Genetics and Genomics [ACMG] and non-ACMG recommended gene lists), frequencies, and rates of SFs, as well as the effects of SF disclosure on the participants and families of a large pediatric cohort at the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP).
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- 2024
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21. Hearing Loss in Children with 22q11.2 Deletion Syndrome.
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Arganbright J, Crowley TB, Tracy M, Noel-MacDonnell J, Gaiser K, Yaktine L, Moore A, Hamm J, Morrow B, Song H, Giunta V, McGinn DE, Zackai EH, Emanuel B, Elden L, Narayanan S, Raje N, and McDonald-McGinn DM
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Objectives: Hearing loss is considered common in children with 22q11.2 deletion syndrome (22q11.2DS), with a few prior studies reporting a 32%-78% prevalence; mild-moderate conductive hearing loss has been reported most commonly. Overall, however, there remains a paucity of data regarding the frequency, type, age, and progression of hearing loss in children with 22q11.2DS., Methods: Retrospective chart review was completed, and data combined for two large 22q centers. Inclusion criteria were children with 22q11.2DS and a documented audiogram. Data extracted included a laboratory-confirmed chromosome 22q11.2 deletion; co-morbidities; results of all audiograms and radiologic temporal bone imaging; and otologic surgical procedures., Results: One thousand seven hundred sixty-nine charts were reviewed; 775 met inclusion criteria. Of these, 563 (73%) children had at least one abnormal audiogram demonstrating hearing loss. A total of 2,536 audiograms were reviewed; 74% of these showed abnormal hearing in at least one ear. Most of the hearing loss was conductive (right ear 76%; left ear 69%) and mild severity. For the children with SNHL, 90% of all follow-up audiograms were stable without progression. Hearing loss was identified across all pediatric age ranges. Ear tube placement occurred in 39% of children., Conclusion: This study confirms the high incidence of hearing loss for children with 22q11.2DS at some point in their childhood. In our cohort, hearing loss occurred in 73% of children and was most often conductive and mild in severity. The results highlight the importance of otolaryngology and audiology involvement in managing children with 22q11.2DS for timely diagnosis and treatment of hearing loss., Level of Evidence: 4 Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)
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- 2024
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22. Phenotypic spectrum and tumor risk in Simpson-Golabi-Behmel syndrome: Case series and comprehensive literature review.
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Nisbet AF, Viswanathan A, George AM, Arias P, Klein SD, Nevado J, Parra A, Pascual P, Romeo DJ, Tenorio-Castaño J, Taylor JA, Zackai EH, Lapunzina P, and Kalish JM
- Abstract
Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population. In addition, we discuss the phenotypic overlap between SGBS and Beckwith-Wiedemann Spectrum., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2024
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23. Utility of genome sequencing in exome-negative pediatric patients with neurodevelopmental phenotypes.
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Nomakuchi TT, Teferedegn EY, Li D, Muirhead KJ, Dubbs H, Leonard J, Muraresku C, Sergio E, Arnold K, Pizzino A, Skraban CM, Zackai EH, Wang K, Ganetzky RD, Vanderver AL, Ahrens-Nicklas RC, and Bhoj EJK
- Abstract
Exome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to improved detection of structural, copy number, repeat number and non-coding variants. However, GS is less commonly utilized due to higher cost and more intense analysis. Here, we present nine cases of pediatric NDD that were molecularly diagnosed with GS between 2017 and 2022, following non-diagnostic ES. All individuals presented with global developmental delay or regression. Other features present in our cohort included epilepsy, white matter abnormalities, brain malformation and dysmorphic features. Two cases were diagnosed on GS due to newly described gene-disease relationship or variant reclassification (MAPK8IP3, CHD3). Additional features missed on ES that were later detected on GS were: intermediate-size deletions in three cases who underwent ES that were not validated for CNV detection, pathogenic variants within the non-protein coding genes SNORD118 and RNU7-1, pathogenic variant within the promoter region of GJB1, and a coding pathogenic variant within BCAP31 which was not sufficiently covered on ES. GS following non-diagnostic ES led to the identification of pathogenic variants in this cohort of nine cases, four of which would not have been identified by reanalysis alone., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2024
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24. Computer-vision analysis of craniofacial dysmorphology in 22q11.2 deletion syndrome and psychosis spectrum disorders.
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Roalf DR, McDonald-McGinn DM, Jee J, Krall M, Crowley TB, Moberg PJ, Kohler C, Calkins ME, Crow AJD, Fleischer N, Gallagher RS, Gonzenbach V, Clark K, Gur RC, McClellan E, McGinn DE, Mordy A, Ruparel K, Turetsky BI, Shinohara RT, White L, Zackai E, and Gur RE
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- Humans, Female, Male, Adolescent, Child, Young Adult, Adult, Machine Learning, Image Processing, Computer-Assisted, DiGeorge Syndrome genetics, DiGeorge Syndrome physiopathology, Psychotic Disorders genetics, Craniofacial Abnormalities genetics
- Abstract
Background: Minor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders., Methods: Here, 2D digital photographs were collected from 22q11DS (n = 150), PS (n = 55), and typically developing (TD; n = 93) individuals. Photographs were analyzed using two computer-vision techniques: (1) DeepGestalt algorithm (Face2Gene (F2G)) technology to identify the presence of genetically mediated facial disorders, and (2) Emotrics-a semi-automated machine learning technique that localizes and measures facial features., Results: F2G reliably identified patients with 22q11DS; faces of PS patients were matched to several genetic conditions including FragileX and 22q11DS. PCA-derived factor loadings of all F2G scores indicated unique and overlapping facial patterns that were related to both 22q11DS and PS. Regional facial measurements of the eyes and nose were smaller in 22q11DS as compared to TD, while PS showed intermediate measurements., Conclusions: The extent to which craniofacial dysmorphology 22q11DS and PS overlapping and evident before the impairment or distress of sub-psychotic symptoms may allow us to identify at-risk youths more reliably and at an earlier stage of development., (© 2024. The Author(s).)
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- 2024
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25. Personal journeys to and in human genetics and dysmorphology.
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Schwartz CE, Aylsworth AS, Allanson J, Battaglia A, Carey JC, Curry CJ, Davies KE, Eichler EE, Graham JM Jr, Hall B, Hall JG, Holmes LB, Hoyme HE, Hunter A, Innis J, Johnson J, Keppler-Noreuil KM, Leroy JG, Moore C, Nelson DL, Neri G, Opitz JM, Picketts D, Raymond FL, Shalev SA, Stevenson RE, Stumpel CTRM, Sutherland G, Viskochil DH, Weaver DD, and Zackai EH
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- Humans, History, 20th Century, History, 21st Century, Human Genetics, Genetics, Medical
- Abstract
Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies., (© 2024 Wiley Periodicals LLC.)
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- 2024
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26. Risk of meningomyelocele mediated by the common 22q11.2 deletion.
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Vong KI, Lee S, Au KS, Crowley TB, Capra V, Martino J, Haller M, Araújo C, Machado HR, George R, Gerding B, James KN, Stanley V, Jiang N, Alu K, Meave N, Nidhiry AS, Jiwani F, Tang I, Nisal A, Jhamb I, Patel A, Patel A, McEvoy-Venneri J, Barrows C, Shen C, Ha YJ, Howarth R, Strain M, Ashley-Koch AE, Azam M, Mumtaz S, Bot GM, Finnell RH, Kibar Z, Marwan AI, Melikishvili G, Meltzer HS, Mutchinick OM, Stevenson DA, Mroczkowski HJ, Ostrander B, Schindewolf E, Moldenhauer J, Zackai EH, Emanuel BS, Garcia-Minaur S, Nowakowska BA, Stevenson RE, Zaki MS, Northrup H, McNamara HK, Aldinger KA, Phelps IG, Deng M, Glass IA, Morrow B, McDonald-McGinn DM, Sanna-Cherchi S, Lamb DJ, and Gleeson JG
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- Animals, Female, Humans, Male, Mice, DiGeorge Syndrome genetics, Exome Sequencing, Folic Acid administration & dosage, Folic Acid Deficiency complications, Folic Acid Deficiency genetics, Penetrance, Spinal Dysraphism genetics, Risk, Adaptor Proteins, Signal Transducing genetics, Chromosome Deletion, Chromosomes, Human, Pair 22 genetics, Meningomyelocele epidemiology, Meningomyelocele genetics
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Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl , one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.
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- 2024
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27. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.
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Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, van Haaften G, Granger L, Petersen AK, Pérez-Jurado LA, Aznar-Laín G, Aneja A, Hancarova M, Bendova S, Schwarz M, Kremlikova Pourova R, Sedlacek Z, Keena BA, March ME, Hou C, O'Connor N, Bhoj EJ, Harr MH, Lemire G, Boycott KM, Towne M, Li M, Tarnopolsky M, Brady L, Parker MJ, Faghfoury H, Parsley LK, Agolini E, Dentici ML, Novelli A, Wright M, Palmquist R, Lai K, Scala M, Striano P, Iacomino M, Zara F, Cooper A, Maarup TJ, Byler M, Lebel RR, Balci TB, Louie R, Lyons M, Douglas J, Nowak C, Afenjar A, Hoyer J, Keren B, Maas SM, Motazacker MM, Martinez-Agosto JA, Rabani AM, McCormick EM, Falk MJ, Ruggiero SM, Helbig I, Møller RS, Tessarollo L, Tomassoni Ardori F, Palko ME, Hsieh TC, Krawitz PM, Ganapathi M, Gelb BD, Jobanputra V, Wilson A, Greally J, Jacquemont S, Jizi K, Bruel AL, Quelin C, Misra VK, Chick E, Romano C, Greco D, Arena A, Morleo M, Nigro V, Seyama R, Uchiyama Y, Matsumoto N, Taira R, Tashiro K, Sakai Y, Yigit G, Wollnik B, Wagner M, Kutsche B, Hurst AC, Thompson ML, Schmidt R, Randolph L, Spillmann RC, Shashi V, Higginbotham EJ, Cordeiro D, Carnevale A, Costain G, Khan T, Funalot B, Tran Mau-Them F, Fernandez Garcia Moya L, García-Miñaúr S, Osmond M, Chad L, Quercia N, Carrasco D, Li C, Sanchez-Valle A, Kelley M, Nizon M, Jensson BO, Sulem P, Stefansson K, Gorokhova S, Busa T, Rio M, Hadj Habdallah H, Lesieur-Sebellin M, Amiel J, Pingault V, Mercier S, Vincent M, Philippe C, Fatus-Fauconnier C, Friend K, Halligan RK, Biswas S, Rosser J, Shoubridge C, Corbett M, Barnett C, Gecz J, Leppig K, Slavotinek A, Marcelis C, Pfundt R, de Vries BB, van Slegtenhorst MA, Brooks AS, Cogne B, Rambaud T, Tümer Z, Zackai EH, Akizu N, Song Y, and Hakonarson H
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- Humans, Gene Regulatory Networks, Mutation, Missense, RNA Splicing, RNA Splicing Factors genetics, Nuclear Proteins genetics, DNA Repair Enzymes genetics, Spliceosomes genetics, Neurodevelopmental Disorders genetics
- Abstract
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
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- 2024
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