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171 results on '"Parenti, Ilaria"'

1. Menke-Hennekam syndrome; delineation of domain-specific subtypes with distinct clinical and DNA methylation profiles

Author

Angius, Andrea, Baker, Janice A., Bedoukian, Emma, Bhambhani, Vikas, Bodamer, Olaf, O’Brien, Alan, Clayton-Smith, Jill, Crisponi, Laura, Cueto González, Anna María, the DDD study, Devriendt, Koenraad, Garrido, Elena Dominguez, Ehmke, Nadja, van Eerde, Albertien, van den Elzen, Annette P.M., Faivre, Laurence, Fisher, Laura, Flores-Daboub, Josue A., Foster, Alison, Friedman, Jennifer, Gabau, Elisabeth, Galazzi, Elena, García-Miñaúr, Sixto, Garavelli, Livia, Gardeitchik, Thatjana, Gerkes, Erica H., van Gils, Julien, Giltay, Jacques C., Garcia, Aixa Gonzalez, Heimdal, Ketil Riddervold, Horn, Denise, Houge, Gunnar, Hufnagel, Sophia B., Ilencikova, Denisa, Julia, Sophie, Kant, Sarina G., Kinning, Esther, Klee, Eric W., Kois, Chelsea, Kovačević, Maja, Lachmeijer, A.M.A. (Guus), Lanpher, Brendan, Lebrun, Marine, Leon, Eyby, Lichty, Angie Ward, Lin, Ruth, Llano-Rivas, Isabel, Lynch, Sally Ann, Maas, Saskia M., Maitz, Silvia B., McKee, Shane, Melis, Daniela, Merati, Elisabetta, Merla, Giuseppe, Newbury-Ecob, Ruth, Nizon, Mathilde, Park, Soo-Mi, Patterson, Jennifer, Petit, Florence, Peeters, Hilde, Persani, Luca, Persico, Ivana, Pes, Valentina, Pollazzon, Marzia, Potjer, Thomas, Potocki, Lorraine, Pottinger, Carrie, Prasad, Chitra, Prijoles, Eloise J., Ragge, Nicola K., Rake, Jan Peter, van Ravenswaaij-Arts, Conny M.A., Rea, Gillian, Ruivenkamp, Claudia, Rutz, Audrey, Saitta, Sulagna C., Russo, Rossana Sanchez, Santen, Gijs W.E., Schaefer, Elise, Shashi, Vandana, Schultz-Rogers, Laura, Sluga, Andrea, Sotgiu, Stefano, Steichen-Gersdorf, Elisabeth, Sullivan, Jennifer A., Sun, Yu, Suri, Mohnish, Tartaglia, Marco, Tedder, Matt, Terhal, Paulien, Tully, Ian, Verbeek, Nienke, Wenzel, Maren, White, Susan M., Xiao, Bing, Haghshenas, Sadegheh, Bout, Hidde J., Schijns, Josephine M., Levy, Michael A., Kerkhof, Jennifer, Bhai, Pratibha, McConkey, Haley, Jenkins, Zandra A., Williams, Ella M., Halliday, Benjamin J., Huisman, Sylvia A., Lauffer, Peter, de Waard, Vivian, Witteveen, Laura, Banka, Siddharth, Brady, Angela F., Hurst, Anna C.E., Kaiser, Frank J., Lacombe, Didier, Martinez-Monseny, Antonio F., Fergelot, Patricia, Monteiro, Fabíola P., Parenti, Ilaria, Santos-Simarro, Fernando, Simpson, Brittany N., Alders, Mariëlle, Robertson, Stephen P., Sadikovic, Bekim, and Menke, Leonie A.

Published
2024
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2. Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X

Author

Leitão, Elsa, Schröder, Christopher, Parenti, Ilaria, Dalle, Carine, Rastetter, Agnès, Kühnel, Theresa, Kuechler, Alma, Kaya, Sabine, Gérard, Bénédicte, Schaefer, Elise, Nava, Caroline, Drouot, Nathalie, Engel, Camille, Piard, Juliette, Duban-Bedu, Bénédicte, Villard, Laurent, Stegmann, Alexander PA, Vanhoutte, Els K, Verdonschot, Job AJ, Kaiser, Frank J, Tran Mau-Them, Frédéric, Scala, Marcello, Striano, Pasquale, Frints, Suzanna GM, Argilli, Emanuela, Sherr, Elliott H, Elder, Fikret, Buratti, Julien, Keren, Boris, Mignot, Cyril, Héron, Delphine, Mandel, Jean-Louis, Gecz, Jozef, Kalscheuer, Vera M, Horsthemke, Bernhard, Piton, Amélie, and Depienne, Christel

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Mental Health, Intellectual and Developmental Disabilities (IDD), Biotechnology, Autism, Human Genome, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Mental health, Humans, Chromosomes, Human, X, Genes, X-Linked, Intellectual Disability, Autism Spectrum Disorder, Databases, Genetic
Abstract

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.

Published
2022

3. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Author

Fountain, Michael D, Oleson, David S, Rech, Megan E, Segebrecht, Lara, Hunter, Jill V, McCarthy, John M, Lupo, Philip J, Holtgrewe, Manuel, Moran, Rocio, Rosenfeld, Jill A, Isidor, Bertrand, Le Caignec, Cédric, Saenz, Margarita S, Pedersen, Robert C, Morgan, Thomas M, Pfotenhauer, Jean P, Xia, Fan, Bi, Weimin, Kang, Sung-Hae L, Patel, Ankita, Krantz, Ian D, Raible, Sarah E, Smith, Wendy, Cristian, Ingrid, Torti, Erin, Juusola, Jane, Millan, Francisca, Wentzensen, Ingrid M, Person, Richard E, Küry, Sébastien, Bézieau, Stéphane, Uguen, Kévin, Férec, Claude, Munnich, Arnold, van Haelst, Mieke, Lichtenbelt, Klaske D, van Gassen, Koen, Hagelstrom, Tanner, Chawla, Aditi, Perry, Denise L, Taft, Ryan J, Jones, Marilyn, Masser-Frye, Diane, Dyment, David, Venkateswaran, Sunita, Li, Chumei, Escobar, Luis F, Horn, Denise, Spillmann, Rebecca C, Peña, Loren, Wierzba, Jolanta, Strom, Tim M, Parenti, Ilaria, Kaiser, Frank J, Ehmke, Nadja, and Schaaf, Christian P

Subjects
Biological Sciences, Genetics, Brain Disorders, Neurosciences, Behavioral and Social Science, Clinical Research, Pediatric, Congenital Structural Anomalies, Intellectual and Developmental Disabilities (IDD), Mental Health, Autism, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Autism Spectrum Disorder, Child, Child, Preschool, Chromosome Deletion, DNA-Binding Proteins, Genome, Human, Haploinsufficiency, Humans, Infant, Infant, Newborn, Intellectual Disability, Language Development Disorders, Neurodevelopmental Disorders, Nuclear Proteins, Phenotype, Problem Behavior, Proteins, Exome Sequencing, USP7, neurodevelopment, speech delay, white matter paucity, corpus callosum thinning, Clinical Sciences, Genetics & Heredity
Abstract

PurposeHaploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling.MethodsWe report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.ResultsThe clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.ConclusionThe consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Published
2019

4. An intragenic duplication in the AFF2 gene associated with Cornelia de Lange syndrome phenotype.

Author

Lucia-Campos, Cristina, Parenti, Ilaria, Latorre-Pellicer, Ana, Gil-Salvador, Marta, Bestetti, Ilaria, Finelli, Palma, Larizza, Lidia, Arnedo, María, Ayerza-Casas, Ariadna, Del Rincón, Julia, Trujillano, Laura, Morte, Beatriz, Pérez-Jurado, Luis A., Lapunzina, Pablo, Leitão, Elsa, Beygo, Jasmin, Lich, Christina, Kilpert, Fabian, Kaya, Sabine, and Depienne, Christel

Subjects
COMPARATIVE genomic hybridization, DIZYGOTIC twins, MOLECULAR diagnosis, GENE expression, CONGENITAL disorders
Abstract

Cornelia de Lange syndrome (CdLS, OMIM #122470, #300590, #300882, #610759, and #614701) is a rare congenital disorder that affects the development of multiple organs and is characterized by physical abnormalities and cognitive and behavioral disabilities. Its molecular basis is mainly based on alterations in genes encoding structural and regulatory proteins related to the cohesin complex. Moreover, other transcriptional regulatory factors have been linked to this syndrome. However, additional causative genes are still unknown, since many patients still lack a molecular diagnosis. Herein, we describe a case with multiple affected family members presenting with an intragenic duplication in the AFF2 gene. The direct tandem intragenic duplication of exons 10, 11 and 12 was detected through high-resolution array Comparative Genomic Hybridization and next-generation sequencing technologies. Confirming the X-linked inheritance pattern, the duplication was found in the patient, his mother and his maternal aunt affected (dizygotic twins). Targeted sequencing with Oxford Nanopore Technologies revealed an aberrant transcript which is predominantly expressed in the patient and his aunt. Along with these results, a significant reduction in AFF2 gene expression levels was detected in these two individuals. Clinically both subjects exhibit a classic CdLS phenotype, whereas the mother is mostly unaffected. Consistent with the phenotypical differences observed between the mother and the aunt, there is a marked difference in X-inactivation patterns skewing. Given the crucial role of AFF2 in transcriptional regulation, it is not surprising that AFF2 variants can give rise to CdLS phenotypes. Therefore, the AFF2 gene should be considered for the molecular diagnosis of this syndrome. [ABSTRACT FROM AUTHOR]

Published
2024
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6. MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome

Author

Parenti, Ilaria, Diab, Farah, Gil, Sara Ruiz, Mulugeta, Eskeatnaf, Casa, Valentina, Berutti, Riccardo, Brouwer, Rutger W.W., Dupé, Valerie, Eckhold, Juliane, Graf, Elisabeth, Puisac, Beatriz, Ramos, Feliciano, Schwarzmayr, Thomas, Gines, Macarena Moronta, van Staveren, Thomas, van IJcken, Wilfred F.J., Strom, Tim M., Pié, Juan, Watrin, Erwan, Kaiser, Frank J., and Wendt, Kerstin S.

Published
2020
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7. Assessment of Quality of Life Using the Kidslife Scale in Individuals With Cornelia de Lange Syndrome

Author

Trujillano, Laura, primary, Ayerza-Casas, Ariadna, additional, Puisac, Beatriz, additional, Latorre-Pellicer, Ana, additional, Arnedo, María, additional, Lucia-Campos, Cristina, additional, Gil-Salvador, Marta, additional, Parenti, Ilaria, additional, Kaiser, Frank J, additional, Ramos, Feliciano J, additional, Trujillano, Javier, additional, and Pié, Juan, additional

Published
2024
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8. Menke-Hennekam syndrome; delineation of domain-specific subtypes with distinct clinical and DNA methylation profiles

Author

Haghshenas, Sadegheh, primary, Bout, Hidde J., additional, Schijns, Josephine M., additional, Levy, Michael A., additional, Kerkhof, Jennifer, additional, Bhai, Pratibha, additional, McConkey, Haley, additional, Jenkins, Zandra A., additional, Williams, Ella M., additional, Halliday, Benjamin J., additional, Huisman, Sylvia A., additional, Lauffer, Peter, additional, de Waard, Vivian, additional, Witteveen, Laura, additional, Banka, Siddharth, additional, Brady, Angela F., additional, Galazzi, Elena, additional, van Gils, Julien, additional, Hurst, Anna C.E., additional, Kaiser, Frank J., additional, Lacombe, Didier, additional, Martinez-Monseny, Antonio F., additional, Fergelot, Patricia, additional, Monteiro, Fabíola P., additional, Parenti, Ilaria, additional, Persani, Luca, additional, Simarro, Fernando Santos, additional, Simpson, Brittany N., additional, Alders, Mariëlle, additional, Robertson, Stephen P., additional, Sadikovic, Bekim, additional, and Menke, Leonie A., additional

Published
2024
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9. Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood

Author

Latorre-Pellicer, Ana, Gil-Salvador, Marta, Parenti, Ilaria, Lucia-Campos, Cristina, Trujillano, Laura, Marcos-Alcalde, Iñigo, Arnedo, María, Ascaso, Ángela, Ayerza-Casas, Ariadna, Antoñanzas-Pérez, Rebeca, Gervasini, Cristina, Piccione, Maria, Mariani, Milena, Weber, Axel, Kanber, Deniz, Kuechler, Alma, Munteanu, Martin, Khuller, Katharina, Bueno-Lozano, Gloria, Puisac, Beatriz, Gómez-Puertas, Paulino, Selicorni, Angelo, Kaiser, Frank J., Ramos, Feliciano J., and Pié, Juan

Published
2021
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10. Quality of Life Evaluation Using the Kidslife Scale in Individuals with Cornelia de Lange Syndrome

Author

Trujillano, Laura, primary, Ayerza-Casas, Ariadna, additional, Puisac, Beatriz, additional, Latorre-Pellicer, Ana, additional, Arnedo, María, additional, Lucia-Campos, Cristina, additional, Gil-Salvador, Marta, additional, Parenti, Ilaria, additional, Kaiser, Frank J., additional, Ramos, Feliciano J., additional, Trujillano, Javier, additional, and Pié, Juan, additional

Published
2024
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11. Endocrine Evaluation and Homeostatic Model Assessment in Patients with Cornelia de Lange Syndrome.

Author

Ascaso, Ángela, Latorre-Pellicer, Ana, Puisac, Beatriz, Trujillano, Laura, Arnedo, María, Parenti, Ilaria, Llorente, Elena, José Puente-Lanzarote, Juan, Matute-Llorente, Ángel, Ayerza-Casas, Ariadna, Kaiser, Frank J., Ramos, Feliciano J., Pié Juste, Juan, and Bueno-Lozano, Gloria

Subjects
HEALTH literacy, DE Lange's syndrome, HOMEOSTASIS, HORMONES, BODY mass index, RARE diseases, DESCRIPTIVE statistics, DEVELOPMENTAL disabilities, INSULIN resistance, RESEARCH methodology, METABOLIC syndrome, ENDOCRINE diseases, ANTHROPOMETRY, CRYPTORCHISM, PITUITARY diseases, HYPOTHYROIDISM, CONNECTIVE tissue growth factor, DISEASE risk factors
Abstract

The aim of this study was to expand knowledge about endocrine disorders in individuals with Cornelia de Lange syndrome (CdLS), a rare developmental genetic disorder with anomalies in multiple organs and systems. Hormone levels, clinical scores, anthropometric measurements, and molecular analysis were assessed in 24 individuals with CdLS. Hyperprolactinemia was the most common endocrine disorder. Three patients showed subclinical hypothyroidism. Concerning the gonadotropic axis, mildly delayed puberty was observed, as well as genital anomalies, such as cryptorchidism. Despite short stature, levels of insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 tended to be normal. Three prepubertal individuals without risk factors had higher than normal values for the homeostatic model assessment of insulin resistance (HOMA-IR) and for insulinemia, suggesting insulin resistance. Furthermore, two adults had elevated body mass indexes associated with HOMA-IR values over the cut-off values. CdLS may lead to dysregulation of the endocrine system, particularly in patients with high HOMA-IR values and insulinemia who are at risk of insulin resistance. Therefore, clinical follow-up with comprehensive hormonal assessment appears warranted in individuals with CdLS. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Author

Sheppard, Sarah E., Bryant, Laura, Wickramasekara, Rochelle N., Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi, Hulen, Jason, Watson, Cynthia J., Faundes, Victor, Duffourd, Yannis, Lee, Pearl, Celeste Simon, M., de la Cruz, Xavier, Padilla, Natália, Flores-Mendez, Marco, Akizu, Naiara, Smiler, Jacqueline, Da Silva, Renata Pellegrino, Li, Dong, March, Michael, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto, Choa, Zhao Xiang, Lim, Chin Yan, Dubourg, Christèle, Journel, Hubert, Demurger, Florence, Mulhern, Maureen, Akman, Cigdem, Lippa, Natalie, Andrews, Marisa, Baldridge, Dustin, Constantino, John, van Haeringen, Arie, Snoeck-Streef, Irina, Chow, Penny, Hing, Anne, Graham, John M., Au, Margaret, Faivre, Laurence, Shen, Wei, Mao, Rong, Palumbos, Janice, Viskochil, David, Gahl, William, Tifft, Cynthia, Macnamara, Ellen, Hauser, Natalie, Miller, Rebecca, Maffeo, Jessica, Afenjar, Alexandra, Doummar, Diane, Keren, Boris, Arn, Pamela, Macklin-Mantia, Sarah, Meerschaut, Ilse, Callewaert, Bert, Reis, André, Zweier, Christiane, Brewer, Carole, Saggar, Anand, Smeland, Marie F., Kumar, Ajith, Elmslie, Frances, Deshpande, Charu, Nizon, Mathilde, Cogne, Benjamin, van Ierland, Yvette, Wilke, Martina, van Slegtenhorst, Marjon, Koudijs, Suzanne, Chen, Jin Yun, Dredge, David, Pier, Danielle, Wortmann, Saskia, Kamsteeg, Erik Jan, Koch, Johannes, Haynes, Devon, Pollack, Lynda, Titheradge, Hannah, Ranguin, Kara, Denommé-Pichon, Anne Sophie, Weber, Sacha, de la Fuente, Rubén Pérez, del Pozo, Jaime Sánchez, Rosales, Jose Miguel Lezana, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Mei, Davide, Mari, Francesco, Guerrini, Renzo, Lespinasse, James, Mau-Them, Frédéric Tran, Philippe, Christophe, Dauriat, Benjamin, Raymond, Laure, Moutton, Sébastien, Cueto-González, Anna M., Tan, Tiong Yang, Mignot, Cyril, Grotto, Sarah, Renaldo, Florence, Drivas, Theodore G., Hennessy, Laura, Raper, Anna, Parenti, Ilaria, Kaiser, Frank J., Kuechler, Alma, Busk, Øyvind L., Islam, Lily, Siedlik, Jacob A., Henderson, Lindsay B., Juusola, Jane, Person, Richard, Schnur, Rhonda E., Vitobello, Antonio, Banka, Siddharth, Bhoj, Elizabeth J., Stessman, Holly A.F., Sheppard, Sarah E., Bryant, Laura, Wickramasekara, Rochelle N., Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi, Hulen, Jason, Watson, Cynthia J., Faundes, Victor, Duffourd, Yannis, Lee, Pearl, Celeste Simon, M., de la Cruz, Xavier, Padilla, Natália, Flores-Mendez, Marco, Akizu, Naiara, Smiler, Jacqueline, Da Silva, Renata Pellegrino, Li, Dong, March, Michael, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto, Choa, Zhao Xiang, Lim, Chin Yan, Dubourg, Christèle, Journel, Hubert, Demurger, Florence, Mulhern, Maureen, Akman, Cigdem, Lippa, Natalie, Andrews, Marisa, Baldridge, Dustin, Constantino, John, van Haeringen, Arie, Snoeck-Streef, Irina, Chow, Penny, Hing, Anne, Graham, John M., Au, Margaret, Faivre, Laurence, Shen, Wei, Mao, Rong, Palumbos, Janice, Viskochil, David, Gahl, William, Tifft, Cynthia, Macnamara, Ellen, Hauser, Natalie, Miller, Rebecca, Maffeo, Jessica, Afenjar, Alexandra, Doummar, Diane, Keren, Boris, Arn, Pamela, Macklin-Mantia, Sarah, Meerschaut, Ilse, Callewaert, Bert, Reis, André, Zweier, Christiane, Brewer, Carole, Saggar, Anand, Smeland, Marie F., Kumar, Ajith, Elmslie, Frances, Deshpande, Charu, Nizon, Mathilde, Cogne, Benjamin, van Ierland, Yvette, Wilke, Martina, van Slegtenhorst, Marjon, Koudijs, Suzanne, Chen, Jin Yun, Dredge, David, Pier, Danielle, Wortmann, Saskia, Kamsteeg, Erik Jan, Koch, Johannes, Haynes, Devon, Pollack, Lynda, Titheradge, Hannah, Ranguin, Kara, Denommé-Pichon, Anne Sophie, Weber, Sacha, de la Fuente, Rubén Pérez, del Pozo, Jaime Sánchez, Rosales, Jose Miguel Lezana, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Mei, Davide, Mari, Francesco, Guerrini, Renzo, Lespinasse, James, Mau-Them, Frédéric Tran, Philippe, Christophe, Dauriat, Benjamin, Raymond, Laure, Moutton, Sébastien, Cueto-González, Anna M., Tan, Tiong Yang, Mignot, Cyril, Grotto, Sarah, Renaldo, Florence, Drivas, Theodore G., Hennessy, Laura, Raper, Anna, Parenti, Ilaria, Kaiser, Frank J., Kuechler, Alma, Busk, Øyvind L., Islam, Lily, Siedlik, Jacob A., Henderson, Lindsay B., Juusola, Jane, Person, Richard, Schnur, Rhonda E., Vitobello, Antonio, Banka, Siddharth, Bhoj, Elizabeth J., and Stessman, Holly A.F.

Abstract

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5Brelated neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Published
2023

14. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Author

Sheppard, Sarah E., primary, Bryant, Laura, additional, Wickramasekara, Rochelle N., additional, Vaccaro, Courtney, additional, Robertson, Brynn, additional, Hallgren, Jodi, additional, Hulen, Jason, additional, Watson, Cynthia J., additional, Faundes, Victor, additional, Duffourd, Yannis, additional, Lee, Pearl, additional, Simon, M. Celeste, additional, de la Cruz, Xavier, additional, Padilla, Natália, additional, Flores-Mendez, Marco, additional, Akizu, Naiara, additional, Smiler, Jacqueline, additional, Pellegrino Da Silva, Renata, additional, Li, Dong, additional, March, Michael, additional, Diaz-Rosado, Abdias, additional, Peixoto de Barcelos, Isabella, additional, Choa, Zhao Xiang, additional, Lim, Chin Yan, additional, Dubourg, Christèle, additional, Journel, Hubert, additional, Demurger, Florence, additional, Mulhern, Maureen, additional, Akman, Cigdem, additional, Lippa, Natalie, additional, Andrews, Marisa, additional, Baldridge, Dustin, additional, Constantino, John, additional, van Haeringen, Arie, additional, Snoeck-Streef, Irina, additional, Chow, Penny, additional, Hing, Anne, additional, Graham, John M., additional, Au, Margaret, additional, Faivre, Laurence, additional, Shen, Wei, additional, Mao, Rong, additional, Palumbos, Janice, additional, Viskochil, David, additional, Gahl, William, additional, Tifft, Cynthia, additional, Macnamara, Ellen, additional, Hauser, Natalie, additional, Miller, Rebecca, additional, Maffeo, Jessica, additional, Afenjar, Alexandra, additional, Doummar, Diane, additional, Keren, Boris, additional, Arn, Pamela, additional, Macklin-Mantia, Sarah, additional, Meerschaut, Ilse, additional, Callewaert, Bert, additional, Reis, André, additional, Zweier, Christiane, additional, Brewer, Carole, additional, Saggar, Anand, additional, Smeland, Marie F., additional, Kumar, Ajith, additional, Elmslie, Frances, additional, Deshpande, Charu, additional, Nizon, Mathilde, additional, Cogne, Benjamin, additional, van Ierland, Yvette, additional, Wilke, Martina, additional, van Slegtenhorst, Marjon, additional, Koudijs, Suzanne, additional, Chen, Jin Yun, additional, Dredge, David, additional, Pier, Danielle, additional, Wortmann, Saskia, additional, Kamsteeg, Erik-Jan, additional, Koch, Johannes, additional, Haynes, Devon, additional, Pollack, Lynda, additional, Titheradge, Hannah, additional, Ranguin, Kara, additional, Denommé-Pichon, Anne-Sophie, additional, Weber, Sacha, additional, Pérez de la Fuente, Rubén, additional, Sánchez del Pozo, Jaime, additional, Lezana Rosales, Jose Miguel, additional, Joset, Pascal, additional, Steindl, Katharina, additional, Rauch, Anita, additional, Mei, Davide, additional, Mari, Francesco, additional, Guerrini, Renzo, additional, Lespinasse, James, additional, Tran Mau-Them, Frédéric, additional, Philippe, Christophe, additional, Dauriat, Benjamin, additional, Raymond, Laure, additional, Moutton, Sébastien, additional, Cueto-González, Anna M., additional, Tan, Tiong Yang, additional, Mignot, Cyril, additional, Grotto, Sarah, additional, Renaldo, Florence, additional, Drivas, Theodore G., additional, Hennessy, Laura, additional, Raper, Anna, additional, Parenti, Ilaria, additional, Kaiser, Frank J., additional, Kuechler, Alma, additional, Busk, Øyvind L., additional, Islam, Lily, additional, Siedlik, Jacob A., additional, Henderson, Lindsay B., additional, Juusola, Jane, additional, Person, Richard, additional, Schnur, Rhonda E., additional, Vitobello, Antonio, additional, Banka, Siddharth, additional, Bhoj, Elizabeth J., additional, and Stessman, Holly A. F., additional

Published
2023
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15. Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes

Author

Parenti, Ilaria, Teresa-Rodrigo, María E., Pozojevic, Jelena, Ruiz Gil, Sara, Bader, Ingrid, Braunholz, Diana, Bramswig, Nuria C., Gervasini, Cristina, Larizza, Lidia, Pfeiffer, Lutz, Ozkinay, Ferda, Ramos, Feliciano, Reiz, Benedikt, Rittinger, Olaf, Strom, Tim M., Watrin, Erwan, Wendt, Kerstin, Wieczorek, Dagmar, Wollnik, Bernd, Baquero-Montoya, Carolina, Pié, Juan, Deardorff, Matthew A., Gillessen-Kaesbach, Gabriele, and Kaiser, Frank J.

Published
2017
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16. PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals

Author

Kampmeier, Antje, primary, Leitão, Elsa, additional, Parenti, Ilaria, additional, Beygo, Jasmin, additional, Depienne, Christel, additional, Bramswig, Nuria C, additional, Hsieh, Tzung-Chien, additional, Afenjar, Alexandra, additional, Beck-Wödl, Stefanie, additional, Grasshoff, Ute, additional, Haack, Tobias B, additional, Bijlsma, Emilia K, additional, Ruivenkamp, Claudia, additional, Lausberg, Eva, additional, Elbracht, Miriam, additional, Haanpää, Maria K, additional, Koillinen, Hannele, additional, Heinrich, Uwe, additional, Rost, Imma, additional, Jamra, Rami Abou, additional, Popp, Denny, additional, Koch-Hogrebe, Margarete, additional, Rostasy, Kevin, additional, López-González, Vanesa, additional, Sanchez-Soler, María José, additional, Macedo, Catarina, additional, Schmetz, Ariane, additional, Steinborn, Carmen, additional, Weidensee, Sabine, additional, Lesmann, Hellen, additional, Marbach, Felix, additional, Caro, Pilar, additional, Schaaf, Christian P., additional, Krawitz, Peter, additional, Wieczorek, Dagmar, additional, Kaiser, Frank J, additional, and Kuechler, Alma, additional

Published
2023
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17. The different clinical facets of SYN1-related neurodevelopmental disorders

Author

Parenti, Ilaria, primary, Leitão, Elsa, additional, Kuechler, Alma, additional, Villard, Laurent, additional, Goizet, Cyril, additional, Courdier, Cécile, additional, Bayat, Allan, additional, Rossi, Alessandra, additional, Julia, Sophie, additional, Bruel, Ange-Line, additional, Tran Mau-Them, Frédéric, additional, Nambot, Sophie, additional, Lehalle, Daphné, additional, Willems, Marjolaine, additional, Lespinasse, James, additional, Ghoumid, Jamal, additional, Caumes, Roseline, additional, Smol, Thomas, additional, El Chehadeh, Salima, additional, Schaefer, Elise, additional, Abi-Warde, Marie-Thérèse, additional, Keren, Boris, additional, Afenjar, Alexandra, additional, Tabet, Anne-Claude, additional, Levy, Jonathan, additional, Maruani, Anna, additional, Aledo-Serrano, Ángel, additional, Garming, Waltraud, additional, Milleret-Pignot, Clara, additional, Chassevent, Anna, additional, Koopmans, Marije, additional, Verbeek, Nienke E., additional, Person, Richard, additional, Belles, Rebecca, additional, Bellus, Gary, additional, Salbert, Bonnie A., additional, Kaiser, Frank J., additional, Mazzola, Laure, additional, Convers, Philippe, additional, Perrin, Laurine, additional, Piton, Amélie, additional, Wiegand, Gert, additional, Accogli, Andrea, additional, Brancati, Francesco, additional, Benfenati, Fabio, additional, Chatron, Nicolas, additional, Lewis-Smith, David, additional, Thomas, Rhys H., additional, Zara, Federico, additional, Striano, Pasquale, additional, Lesca, Gaetan, additional, and Depienne, Christel, additional

Published
2022
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18. Endocrine Evaluation and Homeostatic Model Assessment in Patients with Cornelia de Lange Syndrome

Author

Ascaso, Ángela, primary, Latorre-pellicer, Ana, additional, Puisac, Beatriz, additional, Trujillano, Laura, additional, Arnedo, María, additional, Parenti, Ilaria, additional, Llorente, Elena, additional, Puente-lanzarote, Juan José, additional, Matute-llorente, Ángel, additional, Ayerza-casas, Ariadna, additional, Kaiser, Frank J., additional, Ramos, Feliciano J., additional, Pié, Juan, additional, and Bueno-lozano, Gloria, additional

Published
2022
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20. Cornelia de Lange syndrome and cancer: An open question

Author

Pallotta, Maria M., primary, Di Nardo, Maddalena, additional, Hennekam, Raoul C. M., additional, Kaiser, Frank J., additional, Parenti, Ilaria, additional, Pié, Juan, additional, Ramos, Feliciano J., additional, Kline, Antonie D., additional, and Musio, Antonio, additional

Published
2022
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21. Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Author

Parenti, Ilaria, Lehalle, Daphné, Nava, Caroline, Torti, Erin, Leitão, Elsa, Person, Richard, Mizuguchi, Takeshi, Matsumoto, Naomichi, Kato, Mitsuhiro, Nakamura, Kazuyuki, de Man, Stella A., Cope, Heidi, Shashi, Vandana, Friedman, Jennifer, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Muffels, Irena, van Hasselt, Peter M., Petit, Florence, Smol, Thomas, Le Guyader, Gwenaël, Bilan, Frédéric, Sorlin, Arthur, Vitobello, Antonio, Philippe, Christophe, van de Laar, Ingrid M. B. H., van Slegtenhorst, Marjon A., Campeau, Philippe M., Au, Ping Yee Billie, Nakashima, Mitsuko, Saitsu, Hirotomo, Yamamoto, Tatsuya, Nomura, Yumiko, Louie, Raymond J., Lyons, Michael J., Dobson, Amy, Plomp, Astrid S., Motazacker, M. Mahdi, Kaiser, Frank J., Timberlake, Andrew T., Fuchs, Sabine A., Depienne, Christel, Mignot, Cyril, Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Deardorff, Matthew, Dell’Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldrich, Madison P., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Huryn, Laryssa, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Karaviti, Lefkothea, Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, LaMoure, Grace L., Lanpher, Brendan C., Lanza, Ian R., Latham, Lea, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., MacDowall, John, Macnamara, Ellen F., Mac-Rae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan C., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Mosbrook-Davis, Deborah, Mulvihill, John J., Murdock, David R., Nagy, Anna, Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Power, Bradley, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Shin, Jimann, Signer, Rebecca, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Jennifer A., Sullivan, Kathleen, Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Amelia L. M., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Thurm, Audrey, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yousef, Muhammad, Zastrow, Diane B., Zein, Wadih, Zhao, Chunli, Zuchner, Stephan, Clinical Genetics, Human Genetics, ACS - Pulmonary hypertension & thrombosis, and ANS - Complex Trait Genetics

Subjects
Male, Adolescent, Mutation, Missense, Medizin, Nerve Tissue Proteins, Biology, Frameshift mutation, Chromodomain, Cohort Studies, Young Adult, Epilepsy, Neurodevelopmental disorder, Catalytic Domain, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Child, Genetics (clinical), Exome sequencing, Original Investigation, Genes, Dominant, DNA Helicases, medicine.disease, Pedigree, Neurodevelopmental Disorders, Child, Preschool, Speech delay, Female, medicine.symptom
Abstract

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

Published
2021
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22. Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin–Siris and Nicolaides–Baraitser syndromes

Author

Bramswig, Nuria C., Lüdecke, Hermann-Josef, Alanay, Yasemin, Albrecht, Beate, Barthelmie, Alexander, Boduroglu, Koray, Braunholz, Diana, Caliebe, Almuth, Chrzanowska, Krystyna H., Czeschik, Johanna Christina, Endele, Sabine, Graf, Elisabeth, Guillén-Navarro, Encarna, Kiper, Pelin Özlem Simsek, López-González, Vanesa, Parenti, Ilaria, Pozojevic, Jelena, Utine, Gulen Eda, Wieland, Thomas, Kaiser, Frank J., Wollnik, Bernd, Strom, Tim M., and Wieczorek, Dagmar

Published
2015
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23. Systematic analysis and prediction of genes associated with disorders on chromosome X

Author

Leitão, Elsa, primary, Schröder, Christopher, additional, Parenti, Ilaria, additional, Dalle, Carine, additional, Rastetter, Agnès, additional, Kühnel, Theresa, additional, Kuechler, Alma, additional, Kaya, Sabine, additional, Gérard, Bénédicte, additional, Schaefer, Elise, additional, Nava, Caroline, additional, Drouot, Nathalie, additional, Engel, Camille, additional, Piard, Juliette, additional, Duban-Bedu, Bénédicte, additional, Villard, Laurent, additional, Stegmann, Alexander P.A., additional, Vanhoutte, Els K., additional, Verdonshot, Job A.J, additional, Kaiser, Frank J., additional, Mau-Them, Frédéric Tran, additional, Scala, Marcello, additional, Striano, Pasquale, additional, Frints, Suzanna G.M., additional, Argilli, Emanuela, additional, Sherr, Elliott H., additional, Elder, Fikret, additional, Buratti, Julien, additional, Keren, Boris, additional, Mignot, Cyril, additional, Héron, Delphine, additional, Mandel, Jean-Louis, additional, Gecz, Jozef, additional, Kalscheuer, Vera M., additional, Horsthemke, Bernhard, additional, Piton, Amélie, additional, and Depienne, Christel, additional

Published
2022
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24. Cornelia de Lange Syndrome as Paradigm of Chromatinopathies

Author

Parenti, Ilaria and Kaiser, Frank J.

Subjects
Medizinische Fakultät » Universitätsklinikum Essen » Institut für Humangenetik, transcriptional regulators, chromatinopathies, Mini Review, Medizin, cohesin, ddc:610, chromatin remodelers, Neuroscience, Cornelia de Lange syndrome (CdLS)
Abstract

Chromatinopathies can be defined as a class of neurodevelopmental disorders caused by mutations affecting proteins responsible for chromatin remodeling and transcriptional regulation. The resulting dysregulation of gene expression favors the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disturbances. Cornelia de Lange syndrome (CdLS) is a prime example of a chromatinopathy. It is caused by mutations affecting subunits or regulators of the cohesin complex, a multisubunit protein complex involved in various molecular mechanisms such as sister chromatid cohesion, transcriptional regulation and formation of topologically associated domains. However, disease-causing variants in non-cohesin genes with overlapping functions have also been described in association with CdLS. Notably, the majority of these genes had been previously found responsible for distinct neurodevelopmental disorders that also fall within the category of chromatinopathies and are frequently considered as differential diagnosis for CdLS. In this review, we provide a systematic overview of the current literature to summarize all mutations in non-cohesin genes identified in association with CdLS phenotypes and discuss about the interconnection of proteins belonging to the chromatinopathies network. OA Förderung 2021

Published
2021

25. De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes

Author

Gil-Rodríguez, María Concepción, Deardorff, Matthew A., Ansari, Morad, Tan, Christopher A., Parenti, Ilaria, Baquero-Montoya, Carolina, Ousager, Lilian B., Puisac, Beatriz, Hernández-Marcos, María, Teresa-Rodrigo, María Esperanza, Marcos-Alcalde, Iñigo, Wesselink, Jan-Jaap, Lusa-Bernal, Silvia, Bijlsma, Emilia K., Braunholz, Diana, Bueno-Martinez, Inés, Clark, Dinah, Cooper, Nicola S., Curry, Cynthia J., Fisher, Richard, Fryer, Alan, Ganesh, Jaya, Gervasini, Cristina, Gillessen-Kaesbach, Gabriele, Guo, Yiran, Hakonarson, Hakon, Hopkin, Robert J., Kaur, Maninder, Keating, Brendan J., Kibaek, María, Kinning, Esther, Kleefstra, Tjitske, Kline, Antonie D., Kuchinskaya, Ekaterina, Larizza, Lidia, Li, Yun R., Liu, Xuanzhu, Mariani, Milena, Picker, Jonathan D., Pié, Ángeles, Pozojevic, Jelena, Queralt, Ethel, Richer, Julie, Roeder, Elizabeth, Sinha, Anubha, Scott, Richard H., So, Joyce, Wusik, Katherine A., Wilson, Louise, Zhang, Jianguo, Gómez-Puertas, Paulino, Casale, César H., Ström, Lena, Selicorni, Angelo, Ramos, Feliciano J., Jackson, Laird G., Krantz, Ian D., Das, Soma, Hennekam, Raoul C.M., Kaiser, Frank J., FitzPatrick, David R., and Pié, Juan

Published
2015
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29. Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood

Author

Ministerio de Sanidad (España), Diputación General de Aragón, Latorre-Pellicer, Ana, Gil-Salvador, Marta, Parenti, Ilaria, Lucia-Campos, Cristina, Trujillano, Laura, Marcos-Alcalde, Íñigo, Arnedo, María, Ascaso, Ángela, Ayerza-Casas, Ariadna, Antoñanzas-Peréz, Rebeca, Gervasini, Cristina, Piccione, Maria, Mariani, Milena, Weber, Axel, Kanber, Deniz, Kuechler, Alma, Munteanu, Martin, Khuller, katharina, Bueno-Lozano, Gloria, Puisac, Beatriz, Gómez-Puertas, Paulino, Selicorni, Angelo, Kaiser, Frank J., Ramos, Feliciano J., Pié, Juan, Ministerio de Sanidad (España), Diputación General de Aragón, Latorre-Pellicer, Ana, Gil-Salvador, Marta, Parenti, Ilaria, Lucia-Campos, Cristina, Trujillano, Laura, Marcos-Alcalde, Íñigo, Arnedo, María, Ascaso, Ángela, Ayerza-Casas, Ariadna, Antoñanzas-Peréz, Rebeca, Gervasini, Cristina, Piccione, Maria, Mariani, Milena, Weber, Axel, Kanber, Deniz, Kuechler, Alma, Munteanu, Martin, Khuller, katharina, Bueno-Lozano, Gloria, Puisac, Beatriz, Gómez-Puertas, Paulino, Selicorni, Angelo, Kaiser, Frank J., Ramos, Feliciano J., and Pié, Juan

Abstract

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families.

Published
2021

30. Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Author

Parenti, Ilaria; https://orcid.org/0000-0002-1825-6237, Lehalle, Daphné; https://orcid.org/0000-0002-2193-8685, Nava, Caroline; https://orcid.org/0000-0003-1272-0518, Torti, Erin; https://orcid.org/0000-0001-5790-1051, et al, Undiagnosed Diseases Network, Friedman, Jennifer, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Parenti, Ilaria; https://orcid.org/0000-0002-1825-6237, Lehalle, Daphné; https://orcid.org/0000-0002-2193-8685, Nava, Caroline; https://orcid.org/0000-0003-1272-0518, Torti, Erin; https://orcid.org/0000-0001-5790-1051, et al, Undiagnosed Diseases Network, Friedman, Jennifer, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, and Rauch, Anita; https://orcid.org/0000-0003-2930-3163

Abstract

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

Published
2021

31. Syndromic neurodevelopmental disorder associated with de novo variants inDDX23

Author

Burns, William, primary, Bird, Lynne M., additional, Heron, Delphine, additional, Keren, Boris, additional, Ramachandra, Divya, additional, Thiffault, Isabelle, additional, Del Viso, Florencia, additional, Amudhavalli, Shivarajan, additional, Engleman, Kendra, additional, Parenti, Ilaria, additional, Kaiser, Frank J., additional, Wierzba, Jolanta, additional, Riedhammer, Korbinian M., additional, Liptay, Susanne, additional, Zadeh, Neda, additional, Porrmann, Joseph, additional, Fischer, Andrea, additional, Gößwein, Sophie, additional, McLaughlin, Heather M., additional, Telegrafi, Aida, additional, Langley, Katherine G., additional, Steet, Richard, additional, Louie, Raymond J., additional, and Lyons, Michael J., additional

Published
2021
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32. ANKRD11 variants: KBG syndrome and beyond

Author

Parenti, Ilaria, primary, Mallozzi, Mark B., additional, Hüning, Irina, additional, Gervasini, Cristina, additional, Kuechler, Alma, additional, Agolini, Emanuele, additional, Albrecht, Beate, additional, Baquero‐Montoya, Carolina, additional, Bohring, Axel, additional, Bramswig, Nuria C., additional, Busche, Andreas, additional, Dalski, Andreas, additional, Guo, Yiran, additional, Hanker, Britta, additional, Hellenbroich, Yorck, additional, Horn, Denise, additional, Innes, A. Micheil, additional, Leoni, Chiara, additional, Li, Yun R., additional, Lynch, Sally Ann, additional, Mariani, Milena, additional, Medne, Livija, additional, Mikat, Barbara, additional, Milani, Donatella, additional, Onesimo, Roberta, additional, Ortiz‐Gonzalez, Xilma, additional, Prott, Eva Christina, additional, Reutter, Heiko, additional, Rossier, Eva, additional, Selicorni, Angelo, additional, Wieacker, Peter, additional, Wilkens, Alisha, additional, Wieczorek, Dagmar, additional, Zackai, Elaine H., additional, Zampino, Giuseppe, additional, Zirn, Birgit, additional, Hakonarson, Hakon, additional, Deardorff, Matthew A., additional, Gillessen‐Kaesbach, Gabriele, additional, and Kaiser, Frank J., additional

Published
2021
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34. Heterozygous de novo variants inCSNK1G1are associated with syndromic developmental delay and autism spectrum disorder

Author

Gold, Nina B., primary, Li, Dong, additional, Chassevent, Anna, additional, Kaiser, Frank J., additional, Parenti, Ilaria, additional, Strom, Tim M., additional, Ramos, Feliciano J., additional, Puisac, Beatriz, additional, Pié, Juan, additional, McWalter, Kirsty, additional, Guillen Sacoto, Maria J., additional, Cui, Hong, additional, Saadeh‐Haddad, Reem, additional, Smith‐Hicks, Constance, additional, Rodan, Lance, additional, Blair, Edward, additional, and Bhoj, Elizabeth, additional

Published
2020
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35. Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes

Author

Latorre-Pellicer, Ana, primary, Ascaso, Ángela, additional, Trujillano, Laura, additional, Gil-Salvador, Marta, additional, Arnedo, Maria, additional, Lucia-Campos, Cristina, additional, Antoñanzas-Pérez, Rebeca, additional, Marcos-Alcalde, Iñigo, additional, Parenti, Ilaria, additional, Bueno-Lozano, Gloria, additional, Musio, Antonio, additional, Puisac, Beatriz, additional, Kaiser, Frank J., additional, Ramos, Feliciano J., additional, Gómez-Puertas, Paulino, additional, and Pié, Juan, additional

Published
2020
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36. Front Cover

Author

Avagliano, Laura, primary, Parenti, Ilaria, additional, Grazioli, Paolo, additional, Di Fede, Elisabetta, additional, Parodi, Chiara, additional, Mariani, Milena, additional, Kaiser, Frank J., additional, Selicorni, Angelo, additional, Gervasini, Cristina, additional, and Massa, Valentina, additional

Published
2019
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37. Chromatinopathies: A focus on Cornelia de Lange syndrome

Author

Avagliano, Laura, primary, Parenti, Ilaria, additional, Grazioli, Paolo, additional, Di Fede, Elisabetta, additional, Parodi, Chiara, additional, Mariani, Milena, additional, Kaiser, Frank J., additional, Selicorni, Angelo, additional, Gervasini, Cristina, additional, and Massa, Valentina, additional

Published
2019
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38. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Author

Fountain, Michael D., Oleson, David S., Rech, Megan E., Segebrecht, Lara, Hunter, Jill V., McCarthy, John M., Lupo, Philip J., Holtgrewe, Manuel, Moran, Rocio, Rosenfeld, Jill A., Isidor, Bertrand, Le Caignec, Cédric, Saenz, Margarita S., Pedersen, Robert C., Morgan, Thomas M., Pfotenhauer, Jean P., Xia, Fan, Bi, Weimin, Kang, Sung Hae L., Patel, Ankita, Krantz, Ian D., Raible, Sarah E., Smith, Wendy, Cristian, Ingrid, Torti, Erin, Juusola, Jane, Millan, Francisca, Wentzensen, Ingrid M., Person, Richard E., Küry, Sébastien, Bézieau, Stéphane, Uguen, Kévin, Férec, Claude, Munnich, Arnold, van Haelst, Mieke, Lichtenbelt, Klaske D., van Gassen, Koen, Hagelstrom, Tanner, Chawla, Aditi, Perry, Denise L., Taft, Ryan J., Jones, Marilyn, Masser-Frye, Diane, Dyment, David, Venkateswaran, Sunita, Li, Chumei, Escobar, Luis F., Horn, Denise, Spillmann, Rebecca C., Peña, Loren, Wierzba, Jolanta, Strom, Tim M., Parenti, Ilaria, Kaiser, Frank J., Ehmke, Nadja, Schaaf, Christian P., Fountain, Michael D., Oleson, David S., Rech, Megan E., Segebrecht, Lara, Hunter, Jill V., McCarthy, John M., Lupo, Philip J., Holtgrewe, Manuel, Moran, Rocio, Rosenfeld, Jill A., Isidor, Bertrand, Le Caignec, Cédric, Saenz, Margarita S., Pedersen, Robert C., Morgan, Thomas M., Pfotenhauer, Jean P., Xia, Fan, Bi, Weimin, Kang, Sung Hae L., Patel, Ankita, Krantz, Ian D., Raible, Sarah E., Smith, Wendy, Cristian, Ingrid, Torti, Erin, Juusola, Jane, Millan, Francisca, Wentzensen, Ingrid M., Person, Richard E., Küry, Sébastien, Bézieau, Stéphane, Uguen, Kévin, Férec, Claude, Munnich, Arnold, van Haelst, Mieke, Lichtenbelt, Klaske D., van Gassen, Koen, Hagelstrom, Tanner, Chawla, Aditi, Perry, Denise L., Taft, Ryan J., Jones, Marilyn, Masser-Frye, Diane, Dyment, David, Venkateswaran, Sunita, Li, Chumei, Escobar, Luis F., Horn, Denise, Spillmann, Rebecca C., Peña, Loren, Wierzba, Jolanta, Strom, Tim M., Parenti, Ilaria, Kaiser, Frank J., Ehmke, Nadja, and Schaaf, Christian P.

Published
2019

39. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Author

Genetica, UMC Utrecht, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Fountain, Michael D., Oleson, David S., Rech, Megan E., Segebrecht, Lara, Hunter, Jill V., McCarthy, John M., Lupo, Philip J., Holtgrewe, Manuel, Moran, Rocio, Rosenfeld, Jill A., Isidor, Bertrand, Le Caignec, Cédric, Saenz, Margarita S., Pedersen, Robert C., Morgan, Thomas M., Pfotenhauer, Jean P., Xia, Fan, Bi, Weimin, Kang, Sung Hae L., Patel, Ankita, Krantz, Ian D., Raible, Sarah E., Smith, Wendy, Cristian, Ingrid, Torti, Erin, Juusola, Jane, Millan, Francisca, Wentzensen, Ingrid M., Person, Richard E., Küry, Sébastien, Bézieau, Stéphane, Uguen, Kévin, Férec, Claude, Munnich, Arnold, van Haelst, Mieke, Lichtenbelt, Klaske D., van Gassen, Koen, Hagelstrom, Tanner, Chawla, Aditi, Perry, Denise L., Taft, Ryan J., Jones, Marilyn, Masser-Frye, Diane, Dyment, David, Venkateswaran, Sunita, Li, Chumei, Escobar, Luis F., Horn, Denise, Spillmann, Rebecca C., Peña, Loren, Wierzba, Jolanta, Strom, Tim M., Parenti, Ilaria, Kaiser, Frank J., Ehmke, Nadja, Schaaf, Christian P., Genetica, UMC Utrecht, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Fountain, Michael D., Oleson, David S., Rech, Megan E., Segebrecht, Lara, Hunter, Jill V., McCarthy, John M., Lupo, Philip J., Holtgrewe, Manuel, Moran, Rocio, Rosenfeld, Jill A., Isidor, Bertrand, Le Caignec, Cédric, Saenz, Margarita S., Pedersen, Robert C., Morgan, Thomas M., Pfotenhauer, Jean P., Xia, Fan, Bi, Weimin, Kang, Sung Hae L., Patel, Ankita, Krantz, Ian D., Raible, Sarah E., Smith, Wendy, Cristian, Ingrid, Torti, Erin, Juusola, Jane, Millan, Francisca, Wentzensen, Ingrid M., Person, Richard E., Küry, Sébastien, Bézieau, Stéphane, Uguen, Kévin, Férec, Claude, Munnich, Arnold, van Haelst, Mieke, Lichtenbelt, Klaske D., van Gassen, Koen, Hagelstrom, Tanner, Chawla, Aditi, Perry, Denise L., Taft, Ryan J., Jones, Marilyn, Masser-Frye, Diane, Dyment, David, Venkateswaran, Sunita, Li, Chumei, Escobar, Luis F., Horn, Denise, Spillmann, Rebecca C., Peña, Loren, Wierzba, Jolanta, Strom, Tim M., Parenti, Ilaria, Kaiser, Frank J., Ehmke, Nadja, and Schaaf, Christian P.

Published
2019

40. Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder.

Author

Gold, Nina B., Li, Dong, Chassevent, Anna, Kaiser, Frank J., Parenti, Ilaria, Strom, Tim M., Ramos, Feliciano J., Puisac, Beatriz, Pié, Juan, McWalter, Kirsty, Guillen Sacoto, Maria J., Cui, Hong, Saadeh‐Haddad, Reem, Smith‐Hicks, Constance, Rodan, Lance, Blair, Edward, and Bhoj, Elizabeth

Subjects
DEVELOPMENTAL delay, AUTISM spectrum disorders, EXOMES, COMPARATIVE genomic hybridization, CASEIN kinase, METHYL aspartate receptors
Abstract

The gamma‐1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N‐methyl‐D‐aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early‐onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray‐based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder. [ABSTRACT FROM AUTHOR]

Published
2020
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41. MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover a protective mechanism against early truncating mutations in NIPBL

Author

Parenti, Ilaria, primary, Diab, Farah, additional, Gil, Sara Ruiz, additional, Mulugeta, Eskeatnaf, additional, Casa, Valentina, additional, Berutti, Riccardo, additional, Brouwer, Rutger W.W., additional, Dupé, Valerie, additional, Eckhold, Juliane, additional, Graf, Elisabeth, additional, Puisac, Beatriz, additional, Ramos, Feliciano, additional, Schwarzmayr, Thomas, additional, van Staveren, Thomas, additional, van IJcken, Wilfred F. J., additional, Strom, Tim M., additional, Pié, Juan, additional, Watrin, Erwan, additional, Kaiser, Frank J., additional, and Wendt, Kerstin S., additional

Published
2018
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43. CORNELIA DE LANGE SYNDROME AND RELATED DISORDERS: NEW INSIGHTS INTO GLOBAL TRANSCRIPTIONAL DISTURBANCES DUE TO MUTATIONS IN CHROMATIN-ASSOCIATED FACTORS

Author

PARENTI, ILARIA

Abstract

Cornelia de Lange syndrome (CdLS) is a rare disorder characterized by an extensive clinical heterogeneity. The main features of the syndrome are characteristic facial dysmorphisms and a variable level of intellectual disability, growth retardation and developmental delay. Though, the number and severity of the clinical signs vary among patients. An extensive genetic heterogeneity partially accounts for the reported clinical variability. Mutations in different cohesin-associated proteins are in fact responsible for the onset of the syndrome. The known CdLS-genes include NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Alterations in the cohesin loader NIPBL are found in more than half of CdLS cases and are associated with a classical phenotype and with a high frequency of limb malformations. In addition, mosaicism has been proven to play an important role in association with NIPBL. Mutations in the structural elements SMC1A, SMC3 and RAD21 and in the regulator HDAC8 account for about 10-15% of CdLS cases. The phenotype of those patients who harbor mutations in these genes is usually milder or atypical. The five genes all together, also taking into account the role of mosaicism, can explain about 70% of CdLS cases. In an internationally assembled cohort of patients we were able to identify 109 mutations in NIPBL, 8 mutations in SMC1A, 15 mutations in SMC3 and 11 mutations in HDAC8, thus increasing the total number of mutations so far described for CdLS. In addition, by the use of next generation sequencing techniques we were able to identify mutations in five genes different from cohesin in six unrelated patients with a clinical diagnosis of CdLS. The five genes include those encoding for different subunits of the chromatin remodeling complex named SWI/SNF and for the transcriptional repressor ANKRD11. Mutations in these genes have been so far associated to Coffin-Siris syndrome and KBG syndrome, respectively. Protein-protein interaction experiments also showed a direct interaction of the SWI/SNF subunit SMARCB1 with the cohesin-related proteins NIPBL and SMC3. These direct link between cohesin and SWI/SNF subunits indicate that mutations affecting the two protein complexes might determine the deregulation of overlapping sets of genes. Our newly identified variants contribute to a better understanding of the correlation between genotype and phenotype in the presence of mutations in the known-CdLS genes. Notwithstanding, different pehotypes have been observed in patients carrying the same DNA alteration, hence suggesting that environmental factors may play an important role in the delineation of the observed clinical features. Additionally, the identification of mutations in chromatin-associated factors responsible for syndromes different from CdLS indicate the existence of a broad pleiotropy that should be taken into account while assessing the clinical and molecular diagnosis. Furthermore, we investigated the molecular mechanisms underlying the syndrome in the presence of missense substitutions or small in-frame deletions in SMC1A, a X-linked gene that localizes in a region of the X-chromosome that partially escapes X-inactivation in humans. Our expression analysis revealed that the transcript is expressed at higher levels in females as compared to males, and that there are no differences in the expression of the SMC1A protein between healthy and affected females. In addition, pyrosequencing analysis showed that CdLS female patients harboring mutations in SMC1A tend to express the wild type allele at higher levels as compared to the mutant allele. All together, these data suggests that the pathogenesis of the syndrome in the presence of mutations affecting SMC1A which do not disrupt the reading frame might be linked to a dominant negative effect exerted by the mutant protein on the wild type.

Published
2016
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44. Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype

Author

Parenti, Ilaria, Gervasini, Cristina, Pozojevic, Jelena, Graul-Neumann, Luitgard, Azzollini, Jacopo, Braunholz, Diana, Watrin, Erwan, Wendt, Kerstin S., Cereda, Anna, Cittaro, Davide, Gillessen-Kaesbach, Gabriele, Lazarevic, Dejan, Mariani, Milena, Russo, Silvia, Werner, Ralf, Krawitz, Peter, Larizza, Lidia, Selicorni, Angelo, Kaiser, Frank J., Cell biology, Università degli Studi di Milano = University of Milan (UNIMI), Institut für Humangenetik Lübeck, Universität zu Lübeck = University of Lübeck [Lübeck], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Cell Biology, Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, IRCCS Istituto Auxologico Italiano, Mariani Foundation, Milan, the clinical activity of UOS Pediatric Genetic Clinic of MBBM Foundation Monza, in the frame of E-Rare-2(TARGET-CdLS), the German Federal Ministry of Education and Research (BMBF) (to F. J.K.), the Netherlands Organization for Health Research and Development (ZonMW) (to K. S.W.), the Agence Nationale de la Recherche (ANR) (to E.W.) and the 'Schwerpunktprogramm (SPP) für medizinische Genetik' of the University of Lübeck (to D. B., R.W. and F. J.K.)., Lecoupe-Grainville, Marie, Università degli Studi di Milano [Milano] (UNIMI), Universität zu Lübeck [Lübeck], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Università degli Studi di Milano-Bicocca [Milano] (UNIMIB)

Subjects
Male, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Adolescent, Facies, High-Throughput Nucleotide Sequencing, cohesin, Cornelia de Lange syndrome, ANKRD11, KBG syndrome, whole exome sequencing, Repressor Proteins, Phenotype, mosaicism, Child, Preschool, De Lange Syndrome, Humans, Exome, Female, Genetic Association Studies, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss-of-function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4-year-old girl with features reminiscent of CdLS. Patient B, a 15-year-old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes.

Published
2016
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45. Regulation of the cohesin-loading factor NIPBL: Role of the lncRNA NIPBL-AS1 and identification of a distal enhancer element

Author

Zuin, Jessica, primary, Casa, Valentina, additional, Pozojevic, Jelena, additional, Kolovos, Petros, additional, van den Hout, Mirjam C. G. N., additional, van Ijcken, Wilfred F. J., additional, Parenti, Ilaria, additional, Braunholz, Diana, additional, Baron, Yorann, additional, Watrin, Erwan, additional, Kaiser, Frank J., additional, and Wendt, Kerstin S., additional

Published
2017
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46. Phenotypes and genotypes in individuals with SMC1A variants

Author

Huisman, Sylvia, primary, Mulder, Paul A., additional, Redeker, Egbert, additional, Bader, Ingrid, additional, Bisgaard, Anne‐Marie, additional, Brooks, Alice, additional, Cereda, Anna, additional, Cinca, Constanza, additional, Clark, Dinah, additional, Cormier‐Daire, Valerie, additional, Deardorff, Matthew A., additional, Diderich, Karin, additional, Elting, Mariet, additional, van Essen, Anthonie, additional, FitzPatrick, David, additional, Gervasini, Cristina, additional, Gillessen‐Kaesbach, Gabriele, additional, Girisha, Katta M., additional, Hilhorst‐Hofstee, Yvonne, additional, Hopman, Saskia, additional, Horn, Denise, additional, Isrie, Mala, additional, Jansen, Sandra, additional, Jespersgaard, Cathrine, additional, Kaiser, Frank J., additional, Kaur, Maninder, additional, Kleefstra, Tjitske, additional, Krantz, Ian D., additional, Lakeman, Phillis, additional, Landlust, Annemiek, additional, Lessel, Davor, additional, Michot, Caroline, additional, Moss, Jo, additional, Noon, Sarah E., additional, Oliver, Chris, additional, Parenti, Ilaria, additional, Pie, Juan, additional, Ramos, Feliciano J., additional, Rieubland, Claudine, additional, Russo, Silvia, additional, Selicorni, Angelo, additional, Tümer, Zeynep, additional, Vorstenbosch, Rieneke, additional, Wenger, Tara L., additional, van Balkom, Ingrid, additional, Piening, Sigrid, additional, Wierzba, Jolanta, additional, and Hennekam, Raoul C., additional

Published
2017
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47. Chromatinopathies: A focus on Cornelia de Lange syndrome.

Author

Avagliano, Laura, Parenti, Ilaria, Grazioli, Paolo, Di Fede, Elisabetta, Parodi, Chiara, Mariani, Milena, Kaiser, Frank J., Selicorni, Angelo, Gervasini, Cristina, and Massa, Valentina

Subjects
*GENETIC disorders, *SYNDROMES, *MOLECULAR diagnosis, *RARE diseases
Abstract

In recent years, many genes have been associated with chromatinopathies classified as "Cornelia de Lange Syndrome‐like." It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation. Here, we review the molecular features of Cornelia de Lange syndrome, supporting the hypothesis that "CdLS‐like syndromes" are part of a larger "rare disease family" sharing multiple clinical features and common disrupted molecular pathways. [ABSTRACT FROM AUTHOR]

Published
2020
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48. Phenotypes and genotypes in individuals with SMC1A variants

Author

Huisman, Sylvia, Mulder, Paul A, Redeker, Egbert, Bader, Ingrid, Bisgaard, Anne-Marie, Brooks, Alice, Cereda, Anna, Cinca, Constanza, Clark, Dinah, Cormier-Daire, Valerie, Deardorff, Matthew A, Diderich, Karin, Elting, Mariet, van Essen, Anthonie, FitzPatrick, David, Gervasini, Cristina, Gillessen-Kaesbach, Gabriele, Girisha, Katta M, Hilhorst-Hofstee, Yvonne, Hopman, Saskia, Horn, Denise, Isrie, Mala, Jansen, Sandra, Jespersgaard, Cathrine, Kaiser, Frank J, Kaur, Maninder, Kleefstra, Tjitske, Krantz, Ian D, Lakeman, Phillis, Landlust, Annemiek, Lessel, Davor, Michot, Caroline, Moss, Jo, Noon, Sarah E, Oliver, Chris, Parenti, Ilaria, Pie, Juan, Ramos, Feliciano J, Rieubland, Claudine, Russo, Silvia, Selicorni, Angelo, Tümer, Zeynep, Vorstenbosch, Rieneke, Wenger, Tara L, van Balkom, Ingrid, Piening, Sigrid, Wierzba, Jolanta, Hennekam, Raoul C, Huisman, Sylvia, Mulder, Paul A, Redeker, Egbert, Bader, Ingrid, Bisgaard, Anne-Marie, Brooks, Alice, Cereda, Anna, Cinca, Constanza, Clark, Dinah, Cormier-Daire, Valerie, Deardorff, Matthew A, Diderich, Karin, Elting, Mariet, van Essen, Anthonie, FitzPatrick, David, Gervasini, Cristina, Gillessen-Kaesbach, Gabriele, Girisha, Katta M, Hilhorst-Hofstee, Yvonne, Hopman, Saskia, Horn, Denise, Isrie, Mala, Jansen, Sandra, Jespersgaard, Cathrine, Kaiser, Frank J, Kaur, Maninder, Kleefstra, Tjitske, Krantz, Ian D, Lakeman, Phillis, Landlust, Annemiek, Lessel, Davor, Michot, Caroline, Moss, Jo, Noon, Sarah E, Oliver, Chris, Parenti, Ilaria, Pie, Juan, Ramos, Feliciano J, Rieubland, Claudine, Russo, Silvia, Selicorni, Angelo, Tümer, Zeynep, Vorstenbosch, Rieneke, Wenger, Tara L, van Balkom, Ingrid, Piening, Sigrid, Wierzba, Jolanta, and Hennekam, Raoul C

Abstract

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

Published
2017

49. Hidden Mutations in CdLS - Limitations of Sanger Sequencing in Molecular Diagnostics

Author

Braunholz, Diana, Obieglo, Carolin, Parenti, Ilaria, Pozojevic, Jelena, Eckhold, Juliane, Reiz, Benedikt, Braenne, Ingrid, Wendt, Kerstin S., Watrin, Erwan, Vodopiutz, Julia, Rieder, Harald, Gillessen-Kaesbach, Gabriele, Kaiser, Frank J., Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Department of Clinical Genetics, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Institut für Humangenetik Lübeck, Universität zu Lübeck [Lübeck], TARGET-CdLS, Bundesministerium für Bildung und Forschung, TARGET-CdLS, Netherlands Organisation for Health Research and Development, TARGET-CdLS, Agence Nationale de la Recherche, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Universität zu Lübeck = University of Lübeck [Lübeck]

Subjects
CdLS, panel sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, cohesin, mosaic, NIPBL
Abstract

International audience; Cornelia de Lange syndrome (CdLS) is a well characterized developmental disorder. The genetic cause of CdLS is a mutation in one of five associated genes (NIPBL, SMC1A, SMC3, RAD21 and HDAC8) accounting for about 70 % of cases. To improve our current molecular diagnostic and to analyze some of CdLS candidate genes we developed and established a gene panel approach. Because recent data indicate a high frequency of mosaic NIPBL mutations that were not detected by conventional sequencing approaches of blood DNA, we started to collected buccal mucosa samples of our patients that were negative for mutations in the known CdLS genes. Here we report the identification of three mosaic NIPBL mutations by our high-coverage gene panel sequencing approach that were undetected by classical Sanger sequencing analysis of buccal mucosa DNA. All mutations were confirmed by the use of highly sensitive SNaPshot fragment analysis using DNA from buccal mucosa, urine and fibroblast samples. In blood samples we could not detect the respective mutation. Finally, in fibroblast samples from all three patients, Sanger sequencing could identify all the mutations. Thus, our study highlights the need for highly sensitive technologies in molecular diagnostic of CdLS to improve genetic diagnosis and counseling of patients and their families. This article is protected by copyright. All rights reserved.

Published
2015
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