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1. Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant

Author

Gazzin, Andrea, Fornari, Federico, Niceta, Marcello, Leoni, Chiara, Dentici, Maria Lisa, Carli, Diana, Villar, Anna Maria, Calcagni, Giulio, Banaudi, Elena, Massuras, Stefania, Cardaropoli, Simona, Airulo, Elena, Daniele, Paola, Monda, Emanuele, Limongelli, Giuseppe, Riggi, Chiara, Zampino, Giuseppe, Digilio, Maria Cristina, De Luca, Alessandro, Tartaglia, Marco, Ferrero, Giovanni Battista, and Mussa, Alessandro

Published
2024
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2. Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis

Author

Dentici, Maria Lisa, Niceta, Marcello, Lepri, Francesca Romana, Mancini, Cecilia, Priolo, Manuela, Bonnard, Adeline Alice, Cappelletti, Camilla, Leoni, Chiara, Ciolfi, Andrea, Pizzi, Simone, Cordeddu, Viviana, Rossi, Cesare, Ferilli, Marco, Mucciolo, Mafalda, Colona, Vito Luigi, Fauth, Christine, Bellini, Melissa, Biasucci, Giacomo, Sinibaldi, Lorenzo, Briuglia, Silvana, Gazzin, Andrea, Carli, Diana, Memo, Luigi, Trevisson, Eva, Schiavariello, Concetta, Luca, Maria, Novelli, Antonio, Michot, Caroline, Sweertvaegher, Anne, Germanaud, David, Scarano, Emanuela, De Luca, Alessandro, Zampino, Giuseppe, Zenker, Martin, Mussa, Alessandro, Dallapiccola, Bruno, Cavé, Helene, Digilio, Maria Cristina, and Tartaglia, Marco

Published
2024
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3. DNA methylation profiling in Kabuki syndrome: reclassification of germline KMT2D VUS and sensitivity in validating postzygotic mosaicism

Author

Niceta, Marcello, Ciolfi, Andrea, Ferilli, Marco, Pedace, Lucia, Cappelletti, Camilla, Nardini, Claudia, Hildonen, Mathis, Chiriatti, Luigi, Miele, Evelina, Dentici, Maria Lisa, Gnazzo, Maria, Cesario, Claudia, Pisaneschi, Elisa, Baban, Anwar, Novelli, Antonio, Maitz, Silvia, Selicorni, Angelo, Squeo, Gabriella Maria, Merla, Giuseppe, Dallapiccola, Bruno, Tumer, Zeynep, Digilio, Maria Cristina, Priolo, Manuela, and Tartaglia, Marco

Published
2024
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4. Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA

Author

Revencu, Nicole, Eijkelenboom, Astrid, Bracquemart, Claire, Alhopuro, Pia, Armstrong, Judith, Baselga, Eulalia, Cesario, Claudia, Dentici, Maria Lisa, Eyries, Melanie, Frisk, Sofia, Karstensen, Helena Gásdal, Gene-Olaciregui, Nagore, Kivirikko, Sirpa, Lavarino, Cinzia, Mero, Inger-Lise, Michiels, Rodolphe, Pisaneschi, Elisa, Schönewolf-Greulich, Bitten, Wieland, Ilse, Zenker, Martin, and Vikkula, Miikka

Published
2024
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5. Williams–Beuren syndrome shapes the gut microbiota metaproteome

Author

Marzano, Valeria, Levi Mortera, Stefano, Vernocchi, Pamela, Del Chierico, Federica, Marangelo, Chiara, Guarrasi, Valerio, Gardini, Simone, Dentici, Maria Lisa, Capolino, Rossella, Digilio, Maria Cristina, Di Donato, Maddalena, Spasari, Iolanda, Abreu, Maria Teresa, Dallapiccola, Bruno, and Putignani, Lorenza

Published
2023
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6. Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules

Author

Mastromoro, Gioia, Santoro, Claudia, Motta, Marialetizia, Sorrentino, Ugo, Daniele, Paola, Peduto, Cristina, Petrizzelli, Francesco, Tripodi, Martina, Pinna, Valentina, Zanobio, Mariateresa, Rotundo, Giovannina, Bellacchio, Emanuele, Lepri, Francesca, Farina, Antonella, D’Asdia, Maria Cecilia, Piceci-Sparascio, Francesca, Biagini, Tommaso, Petracca, Antonio, Castori, Marco, Melis, Daniela, Accadia, Maria, Traficante, Giovanna, Tarani, Luigi, Fontana, Paolo, Sirchia, Fabio, Paparella, Roberto, Currò, Aurora, Benedicenti, Francesco, Scala, Iris, Dentici, Maria Lisa, Leoni, Chiara, Trevisan, Valentina, Cecconi, Antonella, Giustini, Sandra, Pizzuti, Antonio, Salviati, Leonardo, Novelli, Antonio, Zampino, Giuseppe, Zenker, Martin, Genuardi, Maurizio, Digilio, Maria Cristina, Papi, Laura, Perrotta, Silverio, Nigro, Vincenzo, Castellanos, Elisabeth, Mazza, Tommaso, Trevisson, Eva, Tartaglia, Marco, Piluso, Giulio, and De Luca, Alessandro

Published
2024
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8. Corrigendum: PTCHD1 gene mutation/deletion: the cognitive-behavioral phenotyping of four case reports

Author

Montanaro, Federica Alice Maria, primary, Mandarino, Alessandra, additional, Alesi, Viola, additional, Schwartz, Charles, additional, Sepulveda, Daniela Judith Claps, additional, Skinner, Cindy, additional, Friez, Michael, additional, Piccolo, Gabriele, additional, Novelli, Antonio, additional, Zanni, Ginevra, additional, Dentici, Maria Lisa, additional, Vicari, Stefano, additional, and Alfieri, Paolo, additional

Published
2024
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9. Case report: A new de novo 6q21q22.1 interstitial deletion case in a girl with cerebellar vermis hypoplasia and developmental delay and literature review

Author

Minotti, Chiara, primary, Graziani, Ludovico, additional, Sallicandro, Ester, additional, Digilio, Maria Cristina, additional, Falasca, Roberto, additional, Alesi, Viola, additional, Novelli, Giuseppe, additional, Dentici, Maria Lisa, additional, Loddo, Sara, additional, and Novelli, Antonio, additional

Published
2024
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11. Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2

Author

Faundes, Víctor, Goh, Stephanie, Akilapa, Rhoda, Bezuidenhout, Heidre, Bjornsson, Hans T., Bradley, Lisa, Brady, Angela F., Brischoux-Boucher, Elise, Brunner, Han, Bulk, Saskia, Canham, Natalie, Cody, Declan, Dentici, Maria Lisa, Digilio, Maria Cristina, Elmslie, Frances, Fry, Andrew E., Gill, Harinder, Hurst, Jane, Johnson, Diana, Julia, Sophie, Lachlan, Katherine, Lebel, Robert Roger, Byler, Melissa, Gershon, Eric, Lemire, Edmond, Gnazzo, Maria, Lepri, Francesca Romana, Marchese, Antonia, McEntagart, Meriel, McGaughran, Julie, Mizuno, Seiji, Okamoto, Nobuhiko, Rieubland, Claudine, Rodgers, Jonathan, Sasaki, Erina, Scalais, Emmanuel, Scurr, Ingrid, Suri, Mohnish, van der Burgt, Ineke, Matsumoto, Naomichi, Miyake, Noriko, Benoit, Valérie, Lederer, Damien, and Banka, Siddharth

Published
2021
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12. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author

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.

Published
2024

13. Clinical and molecular cytogenetic studies of five new patients with 20q11q12 deletion and review of the literature: Proposition of two critical regions.

Author

Bensaid, Souad, Bendahmane, Malika, Loddo, Sara, Poke, Gemma, Januel, Louis, Nicolle, Romain, Malan, Valérie, Chatron, Nicolas, Ottombrino, Silvia, Dentici, Maria Lisa, Novelli, Antonio, Digilio, Maria Cristina, and Sanlaville, Damien

Abstract

Deletions of the long arm of chromosome 20 (20q) are rare, with only 16 reported patients displaying a proximal interstitial 20q deletion. A 1.62 Mb minimal critical region at 20q11.2, encompassing three genes GDF5, EPB41L1, and SAMHD1, is proposed to be responsible for this syndrome. The leading clinical features include growth retardation, intractable feeding difficulties with gastroesophageal reflux, hypotonia and psychomotor developmental delay. Common facial dysmorphisms including triangular face, hypertelorism, and hypoplastic alae nasi were additionally reported. Here, we present the clinical and molecular findings of five new patients with proximal interstitial 20q deletions. We analyzed the phenotype and molecular data of all previously reported patients with 20q11.2q12 microdeletions, along with our five new cases. Copy number variation analysis of patients in our cohort has enabled us to identify the second critical region in the 20q11.2q12 region and redefine the first region that is initially identified. The first critical region spans 359 kb at 20q11.2, containing six MIM genes, including two disease‐causing genes, GDF5 and CEP250. The second critical region spans 706 kb at 20q12, encompassing four MIM genes, including two disease‐causing genes, MAFB and TOP1. We propose GDF5 to be the primary candidate gene generating the phenotype of patients with 20q11.2 deletions. Moreover, we hypothesize TOP1 as a potential candidate gene for the second critical region at 20q12. Of note, we cannot exclude the possibility of a synergistic role of other genes involved in the deletion, including a contiguous gene deletion syndrome or position effect affecting both critical regions. Further studies focusing on patients with proximal 20q deletions are required to support our hypothesis. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author

Li, Dong, primary, Wang, Qin, additional, Bayat, Allan, additional, Battig, Mark R., additional, Zhou, Yijing, additional, Bosch, Daniëlle G.M., additional, van Haaften, Gijs, additional, Granger, Leslie, additional, Petersen, Andrea K., additional, Pérez-Jurado, Luis A., additional, Aznar-Laín, Gemma, additional, Aneja, Anushree, additional, Hancarova, Miroslava, additional, Bendova, Sarka, additional, Schwarz, Martin, additional, Kremlíková Pourová, Radka, additional, Sedlacek, Zdenek, additional, Keena, Beth A., additional, March, Michael E., additional, Hou, Cuiping, additional, O'Connor, Nora, additional, Bhoj, Elizabeth J., additional, Harr, Margaret H., additional, Lemire, Gabrielle, additional, Boycott, Kym M., additional, Towne, Meghan C., additional, Li, Megan, additional, Tarnopolsky, Mark, additional, Brady, Lauren, additional, Parker, Michael J., additional, Faghfoury, Hanna, additional, Parsley, Lea Kristin, additional, Agolini, Emanuele, additional, Dentici, Maria Lisa, additional, Novelli, Antonio, additional, Wright, Meredith S., additional, Palmquist, Rachel, additional, Lai, Khanh, additional, Scala, Marcello, additional, Striano, Pasquale, additional, Iacomino, Michele, additional, Zara, Federico, additional, Cooper, Annina, additional, Maarup, Timothy J., additional, Byler, Melissa, additional, Lebel, Robert Roger, additional, Balci, Tugce B., additional, Louie, Raymond J., additional, Lyons, Michael J., additional, Douglas, Jessica, additional, Nowak, Catherine B., additional, Afenjar, Alexandra, additional, Hoyer, Juliane, additional, Keren, Boris, additional, Maas, Saskia M., additional, Motazacker, Mahdi M., additional, Martinez-Agosto, Julian A., additional, Rabani, Ahna M., additional, McCormick, Elizabeth M., additional, Falk, Marni, additional, Ruggiero, Sarah M., additional, Helbig, Ingo, additional, Møller, Rikke S., additional, Tessarollo, Lino, additional, Tomassoni-Ardori, Francesco, additional, Palko, Mary Ellen, additional, Hsieh, Tzung-Chien, additional, Krawitz, Peter M., additional, Ganapathi, Mythily, additional, Gelb, Bruce D., additional, Jobanputra, Vaidehi, additional, Wilson, Ashley, additional, Greally, John, additional, Jacquemont, Sébastien, additional, Jizi, Khadijé, additional, Ange-Line, Bruel, additional, Quelin, Chloé, additional, Misra, Vinod K., additional, Chick, Erika, additional, Romano, Corrado, additional, Greco, Donatella, additional, Arena, Alessia, additional, Morleo, Manuela, additional, Nigro, Vincenzo, additional, Seyama, Rie, additional, Uchiyama, Yuri, additional, Matsumoto, Naomichi, additional, Taira, Ryoji, additional, Tashiro, Katsuya, additional, Sakai, Yasunari, additional, Yigit, Gökhan, additional, Wollnik, Bernd, additional, Wagner, Michael, additional, Kutsche, Barbara, additional, Hurst, Anna C.E., additional, Thompson, Michelle L., additional, Schmidt, Ryan J., additional, Randolph, Linda M., additional, Spillmann, Rebecca C., additional, Shashi, Vandana, additional, Higginbotham, Edward J., additional, Cordeiro, Dawn, additional, Carnevale, Amanda, additional, Costain, Gregory, additional, Khan, Tayyaba, additional, Funalot, Benoît, additional, Tran Mau-Them, Frederic, additional, Fernandez Garcia Moya, Luis, additional, García-Miñaúr, Sixto, additional, Osmond, Matthew, additional, Chad, Lauren, additional, Quercia, Nada, additional, Carrasco, Diana, additional, Li, Chumei, additional, Sanchez-Valle, Amarilis, additional, Kelley, Meghan, additional, Nizon, Mathilde, additional, Jensson, Brynjar O., additional, Sulem, Patrick, additional, Stefansson, Kari, additional, Gorokhova, Svetlana, additional, Busa, Tiffany, additional, Rio, Marlène, additional, Hadj Abdallah, Hamza, additional, Lesieur-Sebellin, Marion, additional, Amiel, Jeanne, additional, Pingault, Véronique, additional, Mercier, Sandra, additional, Vincent, Marie, additional, Philippe, Christophe, additional, Fatus-Fauconnier, Clemence, additional, Friend, Kathryn, additional, Halligan, Rebecca K., additional, Biswas, Sunita, additional, Rosser, Jane M.R., additional, Shoubridge, Cheryl, additional, Corbett, Mark A., additional, Barnett, Christopher, additional, Gecz, Jozef, additional, Leppig, Kathleen A., additional, Slavotinek, Anne, additional, Marcelis, Carlo, additional, Pfundt, Rolph, additional, de Vries, Bert B.A., additional, van Slegtenhorst, Marjon A., additional, Brooks, Alice S., additional, Cogne, Benjamin, additional, Rambaud, Thomas, additional, Tümer, Zeynep, additional, Zackai, Elaine H., additional, Akizu, Naiara, additional, Song, Yuanquan, additional, and Hakonarson, Hakon, additional

Published
2023
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16. Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

Author

Zhang, Li Xin, Lemire, Gabrielle, Gonzaga-Jauregui, Claudia, Molidperee, Sirinart, Galaz-Montoya, Carolina, Liu, David S., Verloes, Alain, Shillington, Amelle G., Izumi, Kosuke, Ritter, Alyssa L., Keena, Beth, Zackai, Elaine, Li, Dong, Bhoj, Elizabeth, Tarpinian, Jennifer M., Bedoukian, Emma, Kukolich, Mary K., Innes, A. Micheil, Ediae, Grace U., Sawyer, Sarah L., Nair, Karippoth Mohandas, Soumya, Para Chottil, Subbaraman, Kinattinkara R., Probst, Frank J., Bassetti, Jennifer A., Sutton, Reid V., Gibbs, Richard A., Brown, Chester, Boone, Philip M., Holm, Ingrid A., Tartaglia, Marco, Ferrero, Giovanni Battista, Niceta, Marcello, Dentici, Maria Lisa, Radio, Francesca Clementina, Keren, Boris, Wells, Constance F., Coubes, Christine, Laquerrière, Annie, Aziza, Jacqueline, Dubucs, Charlotte, Nampoothiri, Sheela, Mowat, David, Patel, Millan S., Bracho, Ana, Cammarata-Scalisi, Francisco, Gezdirici, Alper, Fernandez-Jaen, Alberto, Hauser, Natalie, Zarate, Yuri A., Bosanko, Katherine A., Dieterich, Klaus, Carey, John C., Chong, Jessica X., Nickerson, Deborah A., Bamshad, Michael J., Lee, Brendan H., Yang, Xiang-Jiao, Lupski, James R., and Campeau, Philippe M.

Published
2020
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17. Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology

Author

Garone, Giacomo, Innocenti, Alice, Grasso, Melissa, Mandarino, Alessandra, Capuano, Alessandro, Della Bella, Gessica, Frascarelli, Flaminia, Diodato, Daria, Onesimo, Roberta, Zampino, Giuseppe, Novelli, Antonio, Digilio, Maria Cristina, Bartuli, Andrea, Dentici, Maria Lisa, Parisi, Pasquale, Galosi, Serena, Tonduti, Davide, Bertini, Enrico, Sinibaldi, Lorenzo, and Specchio, Nicola

Published
2024
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19. Congenital Heart Defects in Patients with Molecularly Confirmed Sotos Syndrome.

Author

Calcagni, Giulio, Ferrigno, Federica, Franceschini, Alessio, Dentici, Maria Lisa, Capolino, Rossella, Sinibaldi, Lorenzo, Minotti, Chiara, Micalizzi, Alessia, Alesi, Viola, Novelli, Antonio, Baban, Anwar, Parlapiano, Giovanni, Coviello, Domenico, Versacci, Paolo, Putotto, Carolina, Chinali, Marcello, Drago, Fabrizio, Bartuli, Andrea, Marino, Bruno, and Digilio, Maria Cristina

Subjects
CONGENITAL heart disease, CARDIAC patients, AORTIC valve insufficiency, PATENT ductus arteriosus, AORTIC coarctation, PULMONARY valve, TRICUSPID valve
Abstract

Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15–40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children's Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2–37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed. [ABSTRACT FROM AUTHOR]

Published
2024
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20. PTCHD1 gene mutation/deletion: the cognitive-behavioral phenotyping of four case reports.

Author

Montanaro, Federica Alice Maria, Mandarino, Alessandra, Alesi, Viola, Schwartz, Charles, Sepulveda, Daniela Judith Claps, Skinner, Cindy, Friez, Michael, Piccolo, Gabriele, Novelli, Antonio, Zanni, Ginevra, Dentici, Maria Lisa, Vicari, Stefano, and Alfieri, Paolo

Subjects
GENETIC mutation, AUTISM spectrum disorders, GENETIC variation, INTELLECTUAL disabilities, PHENOTYPIC plasticity
Abstract

Introduction: X-linked PTCHD1 gene has recently been pointed as one of the most interesting candidates for involvement in neurodevelopmental disorders (NDs), such as intellectual disability (ID) and autism spectrum disorder (ASD). PTCHD1 encodes the patched domain-containing protein 1 (PTCHD1), which is mainly expressed in the developing brain and adult brain tissues. To date, major studies have focused on the biological function of the PTCHD1 gene, while the mechanisms underlying neuronal alterations and the cognitive-behavioral phenotype associated with mutations still remain unclear. Methods: With the aim of incorporating information on the clinical profile of affected individuals and enhancing the characterization of the genotype-phenotype correlation, in this study, we analyze the clinical features of four individuals (two children and two adults) in which array-CGH detected a PTCHD1 deletion or in which panel for screening non-syndromal XLID (X-linked ID) detected a PTCHD1 gene variant. We define the neuropsychological and psychopathological profiles, providing quantitative data from standardized evaluations. The assessment consisted of clinical observations, structured interviews, and parent/self-reported questionnaires. Results: Our descriptive analysis align with previous findings on the involvement of the PTCHD1 gene in NDs. Specifically, our patients exhibited a clinical phenotype characterized by psychomotor developmental delay-ID of varying severity. Interestingly, while ID during early childhood was associated with autistic-like symptomatology, this interrelation was no longer observed in the adult subjects. Furthermore, our cohort did not display peculiar dysmorphic features, congenital abnormalities or comorbidity with epilepsy. Discussion: Our analysis shows that the psychopathological and behavioral comorbidities along with cognitive impairment interfere with development, therefore contributing to the severity of disability associated with PTCHD1 gene mutation. Awareness of this profile by professionals and caregivers can promote prompt diagnosis as well as early cognitive and occupational enhancement interventions. [ABSTRACT FROM AUTHOR]

Published
2024
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21. From Feeding Challenges to Oral-Motor Dyspraxia: A Comprehensive Description of 10 New Cases with CTNNB1 Syndrome

Author

Onesimo, Roberta, primary, Sforza, Elisabetta, additional, Trevisan, Valentina, additional, Leoni, Chiara, additional, Giorgio, Valentina, additional, Rigante, Donato, additional, Kuczynska, Eliza Maria, additional, Proli, Francesco, additional, Agazzi, Cristiana, additional, Limongelli, Domenico, additional, Digilio, Maria Cistina, additional, Dentici, Maria Lisa, additional, Macchiaiolo, Maria, additional, Novelli, Antonio, additional, Bartuli, Andrea, additional, Sinibaldi, Lorenzo, additional, Tartaglia, Marco, additional, and Zampino, Giuseppe, additional

Published
2023
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22. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature

Author

Peluso, Francesca, primary, Caraffi, Stefano G, additional, Contrò, Gianluca, additional, Valeri, Lara, additional, Napoli, Manuela, additional, Carboni, Giorgia, additional, Seth, Alka, additional, Zuntini, Roberta, additional, Coccia, Emanuele, additional, Astrea, Guja, additional, Bisgaard, Anne-Marie, additional, Ivanovski, Ivan, additional, Maitz, Silvia, additional, Brischoux-Boucher, Elise, additional, Carter, Melissa T, additional, Dentici, Maria Lisa, additional, Devriendt, Koenraad, additional, Bellini, Melissa, additional, Digilio, Maria Cristina, additional, Doja, Asif, additional, Dyment, David A, additional, Farholt, Stense, additional, Ferreira, Carlos R, additional, Wolfe, Lynne A, additional, Gahl, William A, additional, Gnazzo, Maria, additional, Goel, Himanshu, additional, Grønborg, Sabine Weller, additional, Hammer, Trine, additional, Iughetti, Lorenzo, additional, Kleefstra, Tjitske, additional, Koolen, David A, additional, Lepri, Francesca Romana, additional, Lemire, Gabrielle, additional, Louro, Pedro, additional, McCullagh, Gary, additional, Madeo, Simona F, additional, Milone, Annarita, additional, Milone, Roberta, additional, Nielsen, Jens Erik Klint, additional, Novelli, Antonio, additional, Ockeloen, Charlotte W., additional, Pascarella, Rosario, additional, Pippucci, Tommaso, additional, Ricca, Ivana, additional, Robertson, Stephen P, additional, Sawyer, Sarah, additional, Falkenberg Smeland, Marie, additional, Stegmann, Sander, additional, Stumpel, Constanze T, additional, Goel, Amy, additional, Taylor, Juliet M, additional, Barbuti, Domenico, additional, Soresina, Annarosa, additional, Bedeschi, Maria Francesca, additional, Battini, Roberta, additional, Cavalli, Anna, additional, Fusco, Carlo, additional, Iascone, Maria, additional, Van Maldergem, Lionel, additional, Venkateswaran, Sunita, additional, Zuffardi, Orsetta, additional, Vergano, Samantha, additional, Garavelli, Livia, additional, and Bayat, Allan, additional

Published
2023
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24. Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.

Author

Sinibaldi, Lorenzo, Garone, Giacomo, Mandarino, Alessandra, Iarossi, Giancarlo, Chioma, Laura, Dentici, Maria Lisa, Merla, Giuseppe, Agolini, Emanuele, Micalizzi, Alessia, Mancini, Cecilia, Niceta, Marcello, Macchiaiolo, Marina, Diodato, Daria, Onesimo, Roberta, Blandino, Rita, Delogu, Angelica Bibiana, De Rosa, Gabriella, Trevisan, Valentina, Iademarco, Mariella, and Zampino, Giuseppe

Subjects
CONGENITAL heart disease, PULMONARY valve, CONSCIOUSNESS raising, HEART septum, MITRAL valve prolapse, CEREBRAL palsy
Abstract

CTNNB1 [OMIM *116806] encodes β‐catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature

Author

Peluso, Francesca; https://orcid.org/0000-0002-0976-1258, Caraffi, Stefano Giuseppe; https://orcid.org/0000-0002-5033-7854, Contrò, Gianluca, Valeri, Lara, Napoli, Manuela, Carboni, Giorgia, Seth, Alka, Zuntini, Roberta, Coccia, Emanuele, Astrea, Guja, Bisgaard, Anne-Marie, Ivanovski, Ivan; https://orcid.org/0000-0002-0113-783X, Maitz, Silvia, Brischoux-Boucher, Elise; https://orcid.org/0000-0002-4816-1431, Carter, Melissa T; https://orcid.org/0000-0001-7211-3731, Dentici, Maria Lisa; https://orcid.org/0000-0002-9505-5906, Devriendt, Koenraad, Bellini, Melissa, Digilio, Maria Cristina, Doja, Asif, Dyment, David A, Farholt, Stense, Ferreira, Carlos R, Wolfe, Lynne A, Gahl, William A, Gnazzo, Maria, Goel, Himanshu, Weller Grønborg, Sabine, Hammer, Trine, Iughetti, Lorenzo, et al, Peluso, Francesca; https://orcid.org/0000-0002-0976-1258, Caraffi, Stefano Giuseppe; https://orcid.org/0000-0002-5033-7854, Contrò, Gianluca, Valeri, Lara, Napoli, Manuela, Carboni, Giorgia, Seth, Alka, Zuntini, Roberta, Coccia, Emanuele, Astrea, Guja, Bisgaard, Anne-Marie, Ivanovski, Ivan; https://orcid.org/0000-0002-0113-783X, Maitz, Silvia, Brischoux-Boucher, Elise; https://orcid.org/0000-0002-4816-1431, Carter, Melissa T; https://orcid.org/0000-0001-7211-3731, Dentici, Maria Lisa; https://orcid.org/0000-0002-9505-5906, Devriendt, Koenraad, Bellini, Melissa, Digilio, Maria Cristina, Doja, Asif, Dyment, David A, Farholt, Stense, Ferreira, Carlos R, Wolfe, Lynne A, Gahl, William A, Gnazzo, Maria, Goel, Himanshu, Weller Grønborg, Sabine, Hammer, Trine, Iughetti, Lorenzo, and et al

Abstract

Background: KBG syndrome is caused by haploinsufficiency of ANKRD11and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. Results: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. Conclusion: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects ofANKRD11variants in skeletal and brain development.

Published
2023

27. DNA methylation profiling in Kabuki syndrome: reclassification of germline KMT2DVUS and sensitivity in validating postzygotic mosaicism

Author

Niceta, Marcello, Ciolfi, Andrea, Ferilli, Marco, Pedace, Lucia, Cappelletti, Camilla, Nardini, Claudia, Hildonen, Mathis, Chiriatti, Luigi, Miele, Evelina, Dentici, Maria Lisa, Gnazzo, Maria, Cesario, Claudia, Pisaneschi, Elisa, Baban, Anwar, Novelli, Antonio, Maitz, Silvia, Selicorni, Angelo, Squeo, Gabriella Maria, Merla, Giuseppe, Dallapiccola, Bruno, Tumer, Zeynep, Digilio, Maria Cristina, Priolo, Manuela, and Tartaglia, Marco

Abstract

Autosomal dominant Kabuki syndrome (KS) is a rare multiple congenital anomalies/neurodevelopmental disorder caused by heterozygous inactivating variants or structural rearrangements of the lysine-specific methyltransferase 2D (KMT2D) gene. While it is often recognizable due to a distinctive gestalt, the disorder is clinically variable, and a phenotypic scoring system has been introduced to help clinicians to reach a clinical diagnosis. The phenotype, however, can be less pronounced in some patients, including those carrying postzygotic mutations. The full spectrum of pathogenic variation in KMT2Dhas not fully been characterized, which may hamper the clinical classification of a portion of these variants. DNA methylation (DNAm) profiling has successfully been used as a tool to classify variants in genes associated with several neurodevelopmental disorders, including KS. In this work, we applied a KS-specific DNAm signature in a cohort of 13 individuals with KMT2DVUS and clinical features suggestive or overlapping with KS. We succeeded in correctly classifying all the tested individuals, confirming diagnosis for three subjects and rejecting the pathogenic role of 10 VUS in the context of KS. In the latter group, exome sequencing allowed to identify the genetic cause underlying the disorder in three subjects. By testing five individuals with postzygotic pathogenic KMT2Dvariants, we also provide evidence that DNAm profiling has power to recognize pathogenic variants at different levels of mosaicism, identifying 15% as the minimum threshold for which DNAm profiling can be applied as an informative diagnostic tool in KS mosaics.

Published
2024
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28. Loss-of-function variants in ERFare associated with a Noonan syndrome-like phenotype with or without craniosynostosis

Author

Dentici, Maria Lisa, Niceta, Marcello, Lepri, Francesca Romana, Mancini, Cecilia, Priolo, Manuela, Bonnard, Adeline Alice, Cappelletti, Camilla, Leoni, Chiara, Ciolfi, Andrea, Pizzi, Simone, Cordeddu, Viviana, Rossi, Cesare, Ferilli, Marco, Mucciolo, Mafalda, Colona, Vito Luigi, Fauth, Christine, Bellini, Melissa, Biasucci, Giacomo, Sinibaldi, Lorenzo, Briuglia, Silvana, Gazzin, Andrea, Carli, Diana, Memo, Luigi, Trevisson, Eva, Schiavariello, Concetta, Luca, Maria, Novelli, Antonio, Michot, Caroline, Sweertvaegher, Anne, Germanaud, David, Scarano, Emanuela, De Luca, Alessandro, Zampino, Giuseppe, Zenker, Martin, Mussa, Alessandro, Dallapiccola, Bruno, Cavé, Helene, Digilio, Maria Cristina, and Tartaglia, Marco

Abstract

Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERFand showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERFhaploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERFcause a “RASopathy” resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy.

Published
2024
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29. A Complex Genomic Rearrangement Resulting in Loss of Function of SCN1A and SCN2A in a Patient with Severe Developmental and Epileptic Encephalopathy

Author

Orlando, Valeria, primary, Di Tommaso, Silvia, additional, Alesi, Viola, additional, Loddo, Sara, additional, Genovese, Silvia, additional, Catino, Giorgia, additional, Martucci, Licia, additional, Roberti, Maria Cristina, additional, Trivisano, Marina, additional, Dentici, Maria Lisa, additional, Specchio, Nicola, additional, Dallapiccola, Bruno, additional, Ferretti, Alessandro, additional, and Novelli, Antonio, additional

Published
2022
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30. MED13 mutation: A novel cause of developmental and epileptic encephalopathy with infantile spasms

Author

Trivisano, Marina, primary, De Dominicis, Angela, additional, Micalizzi, Alessia, additional, Ferretti, Alessandro, additional, Dentici, Maria Lisa, additional, Terracciano, Alessandra, additional, Calabrese, Costanza, additional, Vigevano, Federico, additional, Novelli, Giuseppe, additional, Novelli, Antonio, additional, and Specchio, Nicola, additional

Published
2022
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31. Genotype-phenotype spectrum and correlations in Xia-Gibbs syndrome: Report of five novel cases and literature review

Author

Romano, Ferruccio, Falco, Mariateresa, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Lonardo, Fortunato, Torella, Annalaura, Digilio, Maria Cristina, Dentici, Maria Lisa, Alfieri, Paolo, Agolini, Emanuele, Novelli, Antonio, Garavelli, Livia, Accogli, Andrea, Striano, Pasquale, Scarano, Gioacchino, Nigro, Vincenzo, Scala, Marcello, Capra, Valeria, Romano, Ferruccio, Falco, Mariateresa, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Lonardo, Fortunato, Torella, Annalaura, Digilio, Maria Cristina, Dentici, Maria Lisa, Alfieri, Paolo, Agolini, Emanuele, Novelli, Antonio, Garavelli, Livia, Accogli, Andrea, Striano, Pasquale, Scarano, Gioacchino, Nigro, Vincenzo, Scala, Marcello, and Capra, Valeria

Subjects
Embryology, AHDC1, loss-of-function variant, Genotype, Xia-Gibbs syndrome, Health, Toxicology and Mutagenesis, DNA-Binding Protein, DNA repair, DNA, genotype-phenotype correlation, Toxicology, neurodevelopmental syndrome, Epigenesis, Genetic, Musculoskeletal Abnormalities, Phenotype, Intellectual Disability, Pediatrics, Perinatology and Child Health, Abnormalities, Multiple, Developmental Biology, Human
Abstract

Background Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA-binding motif-containing 1 gene (AHDC1), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. AHDC1 variants possibly act through a dominant-negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N-terminal are thought to determine a milder phenotype with better cognitive performances. However, clean-cut genotype-phenotype correlations are still lacking. Cases In this study, we investigated five subjects with XGS in whom exome sequencing led to the identification of five novel de novo pathogenic variants in AHDC1. All variants were extremely rare and predicted to cause a loss of protein function. The phenotype of the reported patients included developmental delay, hypotonia, and distinctive facial dysmorphisms. Additionally, uncommon clinical features were observed, including congenital hypothyroidism and peculiar skeletal abnormalities. Conclusions In this study, we report uncommon XGS features associated with five novel truncating variants in AHDC, thus expanding the genotype and phenotypic spectrum of this complex condition. We also compared our cases to previously reported cases, discussing the current status of genotype-phenotype correlations in XGS.

Published
2022

34. Analysis of gut microbiota in patients with Williams–Beuren Syndrome reveals dysbiosis linked to clinical manifestations.

Author

Del Chierico, Federica, Marzano, Valeria, Scanu, Matteo, Reddel, Sofia, Dentici, Maria Lisa, Capolino, Rossella, Di Donato, Maddalena, Spasari, Iolanda, Fiscarelli, Ersilia Vita, Digilio, Maria Cristina, Abreu, Maria Teresa, Dallapiccola, Bruno, and Putignani, Lorenza

Subjects
WILLIAMS syndrome, GUT microbiome, SYMPTOMS, DYSBIOSIS, GROWTH disorders, BIFIDOBACTERIUM
Abstract

Williams–Beuren syndrome (WBS) is a multisystem genetic disease caused by the deletion of a region of 1.5–1.8 Mb on chromosome 7q11.23. The elastin gene seems to account for several comorbidities and distinct clinical features such including cardiovascular disease, connective tissue abnormalities, growth retardation, and gastrointestinal (GI) symptoms. Increasing evidence points to alterations in gut microbiota composition as a primary or secondary cause of some GI or extra-intestinal characteristics. In this study, we performed the first exploratory analysis of gut microbiota in WBS patients compared to healthy subjects (CTRLs) using 16S rRNA amplicon sequencing, by investigating the gut dysbiosis in relation to diseases and comorbidities. We found that patients with WBS have significant dysbiosis compared to age-matched CTRLs, characterized by an increase in proinflammatory bacteria such as Pseudomonas, Gluconacetobacter and Eggerthella, and a reduction of anti-inflammatory bacteria including Akkermansia and Bifidobacterium. Microbial biomarkers associated with weight gain, GI symptoms and hypertension were identified. Gut microbiota profiling could represent a new tool that characterise intestinal dysbiosis to complement the clinical management of these patients. In particular, the administration of microbial-based treatments, alongside traditional therapies, could help in reducing or preventing the burden of these symptoms and improve the quality of life of these patients. [ABSTRACT FROM AUTHOR]

Published
2023
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35. Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder

Author

Christensen, Maria B., primary, Levy, Amanda M., additional, Mohammadi, Nazanin A., additional, Niceta, Marcello, additional, Kaiyrzhanov, Rauan, additional, Dentici, Maria Lisa, additional, Al Alam, Chadi, additional, Alesi, Viola, additional, Benoit, Valérie, additional, Bhatia, Kailash P., additional, Bierhals, Tatjana, additional, Boßelmann, Christian M., additional, Buratti, Julien, additional, Callewaert, Bert, additional, Ceulemans, Berten, additional, Charles, Perrine, additional, De Wachter, Matthias, additional, Dehghani, Mohammadreza, additional, D'haenens, Erika, additional, Doco‐Fenzy, Martine, additional, Geßner, Michaela, additional, Gobert, Cyrielle, additional, Guliyeva, Ulviyya, additional, Haack, Tobias B., additional, Hammer, Trine B., additional, Heinrich, Tilman, additional, Hempel, Maja, additional, Herget, Theresia, additional, Hoffmann, Ute, additional, Horvath, Judit, additional, Houlden, Henry, additional, Keren, Boris, additional, Kresge, Christina, additional, Kumps, Candy, additional, Lederer, Damien, additional, Lermine, Alban, additional, Magrinelli, Francesca, additional, Maroofian, Reza, additional, Vahidi Mehrjardi, Mohammad Yahya, additional, Moudi, Mahdiyeh, additional, Müller, Amelie J., additional, Oostra, Anna J., additional, Pletcher, Beth A., additional, Ros‐Pardo, David, additional, Samarasekera, Shanika, additional, Tartaglia, Marco, additional, Van Schil, Kristof, additional, Vogt, Julie, additional, Wassmer, Evangeline, additional, Winkelmann, Juliane, additional, Zaki, Maha S., additional, Zech, Michael, additional, Lerche, Holger, additional, Radio, Francesca Clementina, additional, Gomez‐Puertas, Paulino, additional, Møller, Rikke S., additional, and Tümer, Zeynep, additional

Published
2022
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36. Expanding the novelMAPKAPK5–related developmental disorder's genotype–phenotype correlation: Patient report and 19 months of follow‐up

Author

Vecchio, Davide, primary, Cocciadiferro, Dario, additional, Macchiaiolo, Marina, additional, Gonfiantini, Michaela Veronika, additional, Agolini, Emanuele, additional, Matraxia, Marta, additional, Carboni, Alessia, additional, Coretti, Antonella, additional, Villani, Andrea, additional, Panfili, Filippo Maria, additional, Dentici, Maria Lisa, additional, Buonuomo, Paola Sabrina, additional, Rana, Ippolita, additional, Colafati, Giovanna Stefania, additional, Digilio, Maria Cristina, additional, Novelli, Antonio, additional, and Bartuli, Andrea, additional

Published
2022
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38. Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder

Author

Christensen, Maria B., Levy, Amanda M., Mohammadi, Nazanin A., Niceta, Marcello, Kaiyrzhanov, Rauan, Dentici, Maria Lisa, Al Alam, Chadi, Alesi, Viola, Benoit, Valérie, Bhatia, Kailash P., Bierhals, Tatjana, Boßelmann, Christian M., Buratti, Julien, Callewaert, Bert, Ceulemans, Berten, Charles, Perrine, De Wachter, Matthias, Dehghani, Mohammadreza, D'haenens, Erika, Doco-Fenzy, Martine, Geßner, Michaela, Gobert, Cyrielle, Guliyeva, Ulviyya, Haack, Tobias B., Hammer, Trine B., Heinrich, Tilman, Hempel, Maja, Herget, Theresia, Hoffmann, Ute, Horvath, Judit, Houlden, Henry, Keren, Boris, Kresge, Christina, Kumps, Candy, Lederer, Damien, Lermine, Alban, Magrinelli, Francesca, Maroofian, Reza, Vahidi Mehrjardi, Mohammad Yahya, Moudi, Mahdiyeh, Müller, Amelie J., Oostra, Anna J., Pletcher, Beth A., Ros-Pardo, David, Samarasekera, Shanika, Tartaglia, Marco, Van Schil, Kristof, Vogt, Julie, Wassmer, Evangeline, Winkelmann, Juliane, Zaki, Maha S., Zech, Michael, Lerche, Holger, Radio, Francesca Clementina, Gomez-Puertas, Paulino, Møller, Rikke S., Tümer, Zeynep, Christensen, Maria B., Levy, Amanda M., Mohammadi, Nazanin A., Niceta, Marcello, Kaiyrzhanov, Rauan, Dentici, Maria Lisa, Al Alam, Chadi, Alesi, Viola, Benoit, Valérie, Bhatia, Kailash P., Bierhals, Tatjana, Boßelmann, Christian M., Buratti, Julien, Callewaert, Bert, Ceulemans, Berten, Charles, Perrine, De Wachter, Matthias, Dehghani, Mohammadreza, D'haenens, Erika, Doco-Fenzy, Martine, Geßner, Michaela, Gobert, Cyrielle, Guliyeva, Ulviyya, Haack, Tobias B., Hammer, Trine B., Heinrich, Tilman, Hempel, Maja, Herget, Theresia, Hoffmann, Ute, Horvath, Judit, Houlden, Henry, Keren, Boris, Kresge, Christina, Kumps, Candy, Lederer, Damien, Lermine, Alban, Magrinelli, Francesca, Maroofian, Reza, Vahidi Mehrjardi, Mohammad Yahya, Moudi, Mahdiyeh, Müller, Amelie J., Oostra, Anna J., Pletcher, Beth A., Ros-Pardo, David, Samarasekera, Shanika, Tartaglia, Marco, Van Schil, Kristof, Vogt, Julie, Wassmer, Evangeline, Winkelmann, Juliane, Zaki, Maha S., Zech, Michael, Lerche, Holger, Radio, Francesca Clementina, Gomez-Puertas, Paulino, Møller, Rikke S., and Tümer, Zeynep

Abstract

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

Published
2022

39. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

Author

Kortüm, Fanny, Caputo, Viviana, Bauer, Christiane K, Stella, Lorenzo, Ciolfi, Andrea, Alawi, Malik, Bocchinfuso, Gianfranco, Flex, Elisabetta, Paolacci, Stefano, Dentici, Maria Lisa, Grammatico, Paola, Korenke, Georg Christoph, Leuzzi, Vincenzo, Mowat, David, Nair, Lal D V, Nguyen, Thi Tuyet Mai, Thierry, Patrick, White, Susan M, Dallapiccola, Bruno, Pizzuti, Antonio, Campeau, Philippe M, Tartaglia, Marco, and Kutsche, Kerstin

Published
2015
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40. TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability

Author

Radenkovic, Silvia, primary, Martinelli, Diego, additional, Zhang, Yuebo, additional, Preston, Graeme J., additional, Maiorana, Arianna, additional, Terracciano, Alessandra, additional, Dentici, Maria Lisa, additional, Pisaneschi, Elisa, additional, Novelli, Antonio, additional, Ranatunga, Wasantha, additional, Ligezka, Anna N., additional, Ghesquière, Bart, additional, Deyle, David R., additional, Kozicz, Tamas, additional, Pinto e Vairo, Filippo, additional, Witters, Peter, additional, and Morava, Eva, additional

Published
2022
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41. Congenital heart defects in molecularly confirmed KBG syndrome patients

Author

Digilio, Maria Cristina, primary, Calcagni, Giulio, additional, Gnazzo, Maria, additional, Versacci, Paolo, additional, Dentici, Maria Lisa, additional, Capolino, Rossella, additional, Sinibaldi, Lorenzo, additional, Baban, Anwar, additional, Putotto, Carolina, additional, Alfieri, Paolo, additional, Unolt, Marta, additional, Lepri, Francesca R., additional, Alesi, Viola, additional, Genovese, Silvia, additional, Novelli, Antonio, additional, Marino, Bruno, additional, and Dallapiccola, Bruno, additional

Published
2021
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44. Vascular Birthmarks as a Clue for Complex and Syndromic Vascular Anomalies

Author

Diociaiuti, Andrea, primary, Paolantonio, Guglielmo, additional, Zama, Mario, additional, Alaggio, Rita, additional, Carnevale, Claudia, additional, Conforti, Andrea, additional, Cesario, Claudia, additional, Dentici, Maria Lisa, additional, Buonuomo, Paola Sabrina, additional, Rollo, Massimo, additional, and El Hachem, May, additional

Published
2021
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46. Expanding the novel MAPKAPK5–related developmental disorder's genotype–phenotype correlation: Patient report and 19 months of follow‐up.

Author

Vecchio, Davide, Cocciadiferro, Dario, Macchiaiolo, Marina, Gonfiantini, Michaela Veronika, Agolini, Emanuele, Matraxia, Marta, Carboni, Alessia, Coretti, Antonella, Villani, Andrea, Panfili, Filippo Maria, Dentici, Maria Lisa, Buonuomo, Paola Sabrina, Rana, Ippolita, Colafati, Giovanna Stefania, Digilio, Maria Cristina, Novelli, Antonio, and Bartuli, Andrea

Subjects
CONGENITAL heart disease, CONGENITAL disorders, FINGERS, TOES, HUMAN abnormalities, GENITALIA
Abstract

This study aimed to widen the knowledge of a recently identified, autosomal‐recessive, multiple congenital anomalies syndrome to date observed in only other three children. This is the second report of biallelic mutations in MAPKAPK5 whose impairment during human development has been associated with neurological, cardiac, and facial anomalies combined with fingers and toes malformations. Through the affected patients' genetic and phenotypic features overlap, this report confirms MAPKAPK5 as causative gene and adds unique neurodevelopmental characterization. Moreover, based on the complex congenital genitourinary anomalies reported and MAPKAPK5 literature review, we also propose kidney and external genitalia involvement as a key syndromic feature whose expressivity may be more severe in males. [ABSTRACT FROM AUTHOR]

Published
2022
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48. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, Francesca Clementina, Pang, Kaifang, Ciolfi, Andrea, Levy, Michael A., Hernández-García, Andrés, Pedace, Lucia, Pantaleoni, Francesca, Liu, Zhandong, de Boer, Elke, Jackson, Adam, Bruselles, Alessandro, McConkey, Haley, Stellacci, Emilia, Lo Cicero, Stefania, Motta, Marialetizia, Carrozzo, Rosalba, Dentici, Maria Lisa, McWalter, Kirsty, Desai, Megha, Monaghan, Kristin G., Telegrafi, Aida, Philippe, Christophe, Vitobello, Antonio, Au, Margaret, Grand, Katheryn, Sanchez-Lara, Pedro A., Baez, Joanne, Lindstrom, Kristin, Kulch, Peggy, Sebastian, Jessica, Madan-Khetarpal, Suneeta, Roadhouse, Chelsea, MacKenzie, Jennifer J., Monteleone, Berrin, Saunders, Carol J., Jean Cuevas, July K., Cross, Laura, Zhou, Dihong, Hartley, Taila, Sawyer, Sarah L., Monteiro, Fabíola Paoli, Secches, Tania Vertemati, Kok, Fernando, Schultz-Rogers, Laura E., Macke, Erica L., Morava, Eva, Klee, Eric W., Kemppainen, Jennifer, Iascone, Maria, Selicorni, Angelo, Tenconi, Romano, Amor, David J., Pais, Lynn, Gallacher, Lyndon, Turnpenny, Peter D., Stals, Karen, Ellard, Sian, Cabet, Sara, Lesca, Gaetan, Pascal, Joset, Steindl, Katharina, Ravid, Sarit, Weiss, Karin, Castle, Alison M.R., Carter, Melissa T., Kalsner, Louisa, de Vries, Bert B.A., van Bon, Bregje W., Wevers, Marijke R., Pfundt, Rolph, Stegmann, Alexander P.A., Kerr, Bronwyn, Kingston, Helen M., Chandler, Kate E., Sheehan, Willow, Elias, Abdallah F., Shinde, Deepali N., Towne, Meghan C., Robin, Nathaniel H., Goodloe, Dana, Vanderver, Adeline, Sherbini, Omar, Bluske, Krista, Hagelstrom, R. Tanner, Zanus, Caterina, Faletra, Flavio, Musante, Luciana, Kurtz-Nelson, Evangeline C., Earl, Rachel K., Anderlid, Britt Marie, Morin, Gilles, van Slegtenhorst, Marjon, Diderich, Karin E.M., Brooks, Alice S., Gribnau, Joost, Boers, Ruben G., Finestra, Teresa Robert, Carter, Lauren B., Rauch, Anita, Gasparini, Paolo, Boycott, Kym M., Barakat, Tahsin Stefan, Graham, John M., Faivre, Laurence, Banka, Siddharth, Wang, Tianyun, Eichler, Evan E., Priolo, Manuela, Dallapiccola, Bruno, Vissers, Lisenka E.L.M., Sadikovic, Bekim, Scott, Daryl A., Holder, Jimmy Lloyd, Tartaglia, Marco, Radio, Francesca Clementina, Pang, Kaifang, Ciolfi, Andrea, Levy, Michael A., Hernández-García, Andrés, Pedace, Lucia, Pantaleoni, Francesca, Liu, Zhandong, de Boer, Elke, Jackson, Adam, Bruselles, Alessandro, McConkey, Haley, Stellacci, Emilia, Lo Cicero, Stefania, Motta, Marialetizia, Carrozzo, Rosalba, Dentici, Maria Lisa, McWalter, Kirsty, Desai, Megha, Monaghan, Kristin G., Telegrafi, Aida, Philippe, Christophe, Vitobello, Antonio, Au, Margaret, Grand, Katheryn, Sanchez-Lara, Pedro A., Baez, Joanne, Lindstrom, Kristin, Kulch, Peggy, Sebastian, Jessica, Madan-Khetarpal, Suneeta, Roadhouse, Chelsea, MacKenzie, Jennifer J., Monteleone, Berrin, Saunders, Carol J., Jean Cuevas, July K., Cross, Laura, Zhou, Dihong, Hartley, Taila, Sawyer, Sarah L., Monteiro, Fabíola Paoli, Secches, Tania Vertemati, Kok, Fernando, Schultz-Rogers, Laura E., Macke, Erica L., Morava, Eva, Klee, Eric W., Kemppainen, Jennifer, Iascone, Maria, Selicorni, Angelo, Tenconi, Romano, Amor, David J., Pais, Lynn, Gallacher, Lyndon, Turnpenny, Peter D., Stals, Karen, Ellard, Sian, Cabet, Sara, Lesca, Gaetan, Pascal, Joset, Steindl, Katharina, Ravid, Sarit, Weiss, Karin, Castle, Alison M.R., Carter, Melissa T., Kalsner, Louisa, de Vries, Bert B.A., van Bon, Bregje W., Wevers, Marijke R., Pfundt, Rolph, Stegmann, Alexander P.A., Kerr, Bronwyn, Kingston, Helen M., Chandler, Kate E., Sheehan, Willow, Elias, Abdallah F., Shinde, Deepali N., Towne, Meghan C., Robin, Nathaniel H., Goodloe, Dana, Vanderver, Adeline, Sherbini, Omar, Bluske, Krista, Hagelstrom, R. Tanner, Zanus, Caterina, Faletra, Flavio, Musante, Luciana, Kurtz-Nelson, Evangeline C., Earl, Rachel K., Anderlid, Britt Marie, Morin, Gilles, van Slegtenhorst, Marjon, Diderich, Karin E.M., Brooks, Alice S., Gribnau, Joost, Boers, Ruben G., Finestra, Teresa Robert, Carter, Lauren B., Rauch, Anita, Gasparini, Paolo, Boycott, Kym M., Barakat, Tahsin Stefan, Graham, John M., Faivre, Laurence, Banka, Siddharth, Wang, Tianyun, Eichler, Evan E., Priolo, Manuela, Dallapiccola, Bruno, Vissers, Lisenka E.L.M., Sadikovic, Bekim, Scott, Daryl A., Holder, Jimmy Lloyd, and Tartaglia, Marco

Abstract

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

50. Cognitive and Adaptive Characterization of Children and Adolescents with KBG Syndrome: An Explorative Study

Author

Alfieri, Paolo, primary, Caciolo, Cristina, additional, Lazzaro, Giulia, additional, Menghini, Deny, additional, Cumbo, Francesca, additional, Dentici, Maria Lisa, additional, Digilio, Maria Cristina, additional, Gnazzo, Maria, additional, Demaria, Francesco, additional, Pironi, Virginia, additional, Zampino, Giuseppe, additional, Novelli, Antonio, additional, Tartaglia, Marco, additional, and Vicari, Stefano, additional

Published
2021
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