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1. Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study

Author

Paulet, Alix, Bennett-Ness, Cavan, Ageorges, Faustine, Trost, Detlef, Green, Andrew, Goudie, David, Jewell, Rosalyn, Kraatari-Tiri, Minna, PIARD, Juliette, Coubes, Christine, Lam, Wayne, Lynch, Sally Ann, Groeschel, Samuel, Ramond, Francis, Fluss, Joël, Fagerberg, Christina, Brasch Andersen, Charlotte, Varvagiannis, Konstantinos, Kleefstra, Tjitske, Gérard, Bénédicte, Fradin, Mélanie, Vitobello, Antonio, Tenconi, Romano, Denommé-Pichon, Anne-Sophie, Vincent-Devulder, Aline, Haack, Tobias, Marsh, Joseph A, Laulund, Lone Walentin, Grimmel, Mona, Riess, Angelika, de Boer, Elke, Padilla-Lopez, Sergio, Bakhtiari, Somayeh, Ostendorf, Adam, Zweier, Christiane, Smol, Thomas, Willems, Marjolaine, Faivre, Laurence, Scala, Marcello, Striano, Pasquale, Bagnasco, Irene, Koboldt, Daniel, Iascone, Maria, Suerink, Manon, Kruer, Michael C, Levy, Jonathan, Verloes, Alain, Abbott, Catherine M, and Ruaud, Lyse

Published
2024
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2. Correction: Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study

Author

Paulet, Alix, Bennett-Ness, Cavan, Ageorges, Faustine, Trost, Detlef, Green, Andrew, Goudie, David, Jewell, Rosalyn, Kraatari-Tiri, Minna, PIARD, Juliette, Coubes, Christine, Lam, Wayne, Lynch, Sally Ann, Groeschel, Samuel, Ramond, Francis, Fluss, Joël, Fagerberg, Christina, Brasch Andersen, Charlotte, Varvagiannis, Konstantinos, Kleefstra, Tjitske, Gérard, Bénédicte, Fradin, Mélanie, Vitobello, Antonio, Tenconi, Romano, Denommé-Pichon, Anne-Sophie, Vincent-Devulder, Aline, Haack, Tobias, Marsh, Joseph A, Laulund, Lone Walentin, Grimmel, Mona, Riess, Angelika, de Boer, Elke, Padilla-Lopez, Sergio, Bakhtiari, Somayeh, Ostendorf, Adam, Zweier, Christiane, Smol, Thomas, Willems, Marjolaine, Faivre, Laurence, Scala, Marcello, Striano, Pasquale, Bagnasco, Irene, Koboldt, Daniel, Iascone, Maria, Suerink, Manon, Kruer, Michael C, Levy, Jonathan, Verloes, Alain, Abbott, Catherine M, and Ruaud, Lyse

Published
2024
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3. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Published
2023
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4. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author

Pagnamenta, Alistair T., Camps, Carme, Giacopuzzi, Edoardo, Taylor, John M., Hashim, Mona, Calpena, Eduardo, Kaisaki, Pamela J., Hashimoto, Akiko, Yu, Jing, Sanders, Edward, Schwessinger, Ron, Hughes, Jim R., Lunter, Gerton, Dreau, Helene, Ferla, Matteo, Lange, Lukas, Kesim, Yesim, Ragoussis, Vassilis, Vavoulis, Dimitrios V., Allroggen, Holger, Ansorge, Olaf, Babbs, Christian, Banka, Siddharth, Baños-Piñero, Benito, Beeson, David, Ben-Ami, Tal, Bennett, David L., Bento, Celeste, Blair, Edward, Brasch-Andersen, Charlotte, Bull, Katherine R., Cario, Holger, Cilliers, Deirdre, Conti, Valerio, Davies, E. Graham, Dhalla, Fatima, Dacal, Beatriz Diez, Dong, Yin, Dunford, James E., Guerrini, Renzo, Harris, Adrian L., Hartley, Jane, Hollander, Georg, Javaid, Kassim, Kane, Maureen, Kelly, Deirdre, Kelly, Dominic, Knight, Samantha J. L., Kreins, Alexandra Y., Kvikstad, Erika M., Langman, Craig B., Lester, Tracy, Lines, Kate E., Lord, Simon R., Lu, Xin, Mansour, Sahar, Manzur, Adnan, Maroofian, Reza, Marsden, Brian, Mason, Joanne, McGowan, Simon J., Mei, Davide, Mlcochova, Hana, Murakami, Yoshiko, Németh, Andrea H., Okoli, Steven, Ormondroyd, Elizabeth, Ousager, Lilian Bomme, Palace, Jacqueline, Patel, Smita Y., Pentony, Melissa M., Pugh, Chris, Rad, Aboulfazl, Ramesh, Archana, Riva, Simone G., Roberts, Irene, Roy, Noémi, Salminen, Outi, Schilling, Kyleen D., Scott, Caroline, Sen, Arjune, Smith, Conrad, Stevenson, Mark, Thakker, Rajesh V., Twigg, Stephen R. F., Uhlig, Holm H., van Wijk, Richard, Vona, Barbara, Wall, Steven, Wang, Jing, Watkins, Hugh, Zak, Jaroslav, Schuh, Anna H., Kini, Usha, Wilkie, Andrew O. M., Popitsch, Niko, and Taylor, Jenny C.

Published
2023
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5. National clinical Genetic Networks - GENets - Establishment of expert collaborations in Denmark

Author

Lildballe, Dorte L., Frederiksen, Anja Lisbeth, Schönewolf-Greulich, Bitten, Brasch-Andersen, Charlotte, Lautrup, Charlotte Kvist, Karstensen, Helena Gásdal, Pedersen, Inge Søkilde, Sunde, Lone, Risom, Lotte, Rasmussen, Maria, Bertelsen, Mette, Andersen, Mette Klarskov, Rendtorff, Nanna Dahl, Gregersen, Pernille Axél, Tørring, Pernille M., Hammer-Hansen, Sophia, Boonen, Susanne E., Lindquist, Suzanne Granhøj, Hammer, Trine Bjørg, and Diness, Birgitte R.

Published
2023
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6. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Author

Gillentine, Madelyn A, Wang, Tianyun, Hoekzema, Kendra, Rosenfeld, Jill, Liu, Pengfei, Guo, Hui, Kim, Chang N, De Vries, Bert BA, Vissers, Lisenka ELM, Nordenskjold, Magnus, Kvarnung, Malin, Lindstrand, Anna, Nordgren, Ann, Gecz, Jozef, Iascone, Maria, Cereda, Anna, Scatigno, Agnese, Maitz, Silvia, Zanni, Ginevra, Bertini, Enrico, Zweier, Christiane, Schuhmann, Sarah, Wiesener, Antje, Pepper, Micah, Panjwani, Heena, Torti, Erin, Abid, Farida, Anselm, Irina, Srivastava, Siddharth, Atwal, Paldeep, Bacino, Carlos A, Bhat, Gifty, Cobian, Katherine, Bird, Lynne M, Friedman, Jennifer, Wright, Meredith S, Callewaert, Bert, Petit, Florence, Mathieu, Sophie, Afenjar, Alexandra, Christensen, Celenie K, White, Kerry M, Elpeleg, Orly, Berger, Itai, Espineli, Edward J, Fagerberg, Christina, Brasch-Andersen, Charlotte, Hansen, Lars Kjærsgaard, Feyma, Timothy, Hughes, Susan, Thiffault, Isabelle, Sullivan, Bonnie, Yan, Shuang, Keller, Kory, Keren, Boris, Mignot, Cyril, Kooy, Frank, Meuwissen, Marije, Basinger, Alice, Kukolich, Mary, Philips, Meredith, Ortega, Lucia, Drummond-Borg, Margaret, Lauridsen, Mathilde, Sorensen, Kristina, Lehman, Anna, CAUSES Study, Lopez-Rangel, Elena, Levy, Paul, Lessel, Davor, Lotze, Timothy, Madan-Khetarpal, Suneeta, Sebastian, Jessica, Vento, Jodie, Vats, Divya, Benman, L Manace, Mckee, Shane, Mirzaa, Ghayda M, Muss, Candace, Pappas, John, Peeters, Hilde, Romano, Corrado, Elia, Maurizio, Galesi, Ornella, Simon, Marleen EH, van Gassen, Koen LI, Simpson, Kara, Stratton, Robert, Syed, Sabeen, Thevenon, Julien, Palafoll, Irene Valenzuela, Vitobello, Antonio, Bournez, Marie, Faivre, Laurence, Xia, Kun, SPARK Consortium, Earl, Rachel K, Nowakowski, Tomasz, Bernier, Raphael A, and Eichler, Evan E

Subjects
CAUSES Study, SPARK Consortium, Cortex development, Gene families, Neurodevelopmental disorders, hnRNPs, Genetics, Clinical Sciences
Abstract

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Published
2021

7. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability

Author

Bogaert, Elke, Garde, Aurore, Gautier, Thierry, Rooney, Kathleen, Duffourd, Yannis, LeBlanc, Pontus, van Reempts, Emma, Tran Mau-Them, Frederic, Wentzensen, Ingrid M., Au, Kit Sing, Richardson, Kate, Northrup, Hope, Gatinois, Vincent, Geneviève, David, Louie, Raymond J., Lyons, Michael J., Laulund, Lone Walentin, Brasch-Andersen, Charlotte, Maxel Juul, Trine, El It, Fatima, Marle, Nathalie, Callier, Patrick, Relator, Raissa, Haghshenas, Sadegheh, McConkey, Haley, Kerkhof, Jennifer, Cesario, Claudia, Novelli, Antonio, Brunetti-Pierri, Nicola, Pinelli, Michele, Pennamen, Perrine, Naudion, Sophie, Legendre, Marine, Courdier, Cécile, Trimouille, Aurelien, Fenzy, Martine Doco, Pais, Lynn, Yeung, Alison, Nugent, Kimberly, Roeder, Elizabeth R., Mitani, Tadahiro, Posey, Jennifer E., Calame, Daniel, Yonath, Hagith, Rosenfeld, Jill A., Musante, Luciana, Faletra, Flavio, Montanari, Francesca, Sartor, Giovanna, Vancini, Alessandra, Seri, Marco, Besmond, Claude, Poirier, Karine, Hubert, Laurence, Hemelsoet, Dimitri, Munnich, Arnold, Lupski, James R., Philippe, Christophe, Thauvin-Robinet, Christel, Faivre, Laurence, Sadikovic, Bekim, Govin, Jérôme, Dermaut, Bart, and Vitobello, Antonio

Published
2023
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8. Generation of two patient specific GABRD variants and their isogenic controls for modeling epilepsy

Author

Kamand, Morad, primary, Taleb, Reema, additional, Wathikthinnakon, Methi, additional, Mohamed, Fadumo Abdullahi, additional, Ghazanfari, Said Pasalar, additional, Konstantinov, Denis, additional, Hald, Jonas Laugård, additional, Holst, Bjørn, additional, Brasch-Andersen, Charlotte, additional, Møller, Rikke S., additional, Lemke, Johannes R., additional, Krey, Ilona, additional, Freude, Kristine, additional, and Chandrasekaran, Abinaya, additional

Published
2024
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9. Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome: Five Danish patients with novel variants in AHDC1

Author

Faergeman, Soren L., Bojesen, Anders B., Rasmussen, Maria, Becher, Naja, Andreasen, Lotte, Andersen, Brian N., Erbs, Emilie, Lildballe, Dorte L., Nielsen, Jens Erik K., Zilmer, Monica, Hammer, Trine Bjørg, Andersen, Mikkel Ø., Brasch-Andersen, Charlotte, Fagerberg, Christina R., Illum, Niels O., Thorup, Mette B., and Gregersen, Pernille A.

Published
2021
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11. Generation of two patient specific GABRD variants and their isogenic controls for modeling epilepsy

Author

Kamand, Morad, Taleb, Reema, Wathikthinnakon, Methi, Mohamed, Fadumo Abdullahi, Ghazanfari, Said Pasalar, Konstantinov, Denis, Hald, Jonas Laugård, Holst, Bjørn, Brasch-Andersen, Charlotte, Møller, Rikke S., Lemke, Johannes R., Krey, Ilona, Freude, Kristine, Chandrasekaran, Abinaya, Kamand, Morad, Taleb, Reema, Wathikthinnakon, Methi, Mohamed, Fadumo Abdullahi, Ghazanfari, Said Pasalar, Konstantinov, Denis, Hald, Jonas Laugård, Holst, Bjørn, Brasch-Andersen, Charlotte, Møller, Rikke S., Lemke, Johannes R., Krey, Ilona, Freude, Kristine, and Chandrasekaran, Abinaya

Abstract

Developmental and epileptic encephalopathies (DEEs) are early-onset conditions that cause intractable seizures and developmental delays. Missense variants in Gamma-aminobutyric acid type A receptor (GABAAR) subunits commonly cause DEEs. Ahring et al. (2022) showed a variant in the gene that encodes the delta subunit (GABRD) is strongly associated with the gain-of-function of extrasynaptic GABAAR. Here, we report the generation of two patient-specific human induced pluripotent stem cells (hiPSC) lines with (i) a de novo variant and (ii) a maternal variant, both for the pathogenic GABRD c.872 C>T, (p.T291I). The variants in the generated cell line were corrected using the CRISPR-Cas9 gene editing technique (respective isogenic control lines).

Published
2024

12. Frail inner limiting membrane maculopathy suggested to describe a new retinal Alport-like condition with two variants in three generations of females.

Author

Petersen, Sekita Dalsgård, Belmouhand, Mohamed, Hertz, Jens Michael, Fagerberg, Christina, Brasch-Andersen, Charlotte, Grauslund, Jakob, Munier, Francis L., and Larsen, Michael

Subjects
OPTICAL coherence tomography, SLIT lamp microscopy, WHOLE genome sequencing, VISUAL fields, MACULAR degeneration
Abstract

We report a three-generation family with isolated Alport-like retinal abnormalities in the absence of lenticonus, hearing loss, kidney disease, and detectable molecular genetic defects in known Alport-related genes. Clinical examination includes ocular biomicroscopy, fundus photography, optical coherence tomography, dipstick urinalysis, serum creatinine assessment, and molecular genetic analysis. The proband, her mother, and her maternal grandmother had normal best-corrected visual acuity and normal visual fields in both eyes. The macula presented a petaloid stair-case profile with scarce vessels in both eyes of the proband and a flat temporal macula lacking a foveal avascular zone in her mother and her grandmother. No family member had renal symptoms, unexplained subnormal hearing, or lenticonus. Sequencing and MLPA found no defect in COL4A3, COL4A4, and COL4A5. Common SNPs around the genes ± 1Mb showed no segregation. Furthermore, none of the variants shared between the affected individuals in genes from a gene panel of genes relevant for ophthalmopathy nor whole exome- and genome sequencing explained the phenotype. A new condition with two retinal Alport-like phenotypes was found. No abnormalities of the kidneys and lens were found, neither abnormalities of the type IV collagen genes related to Alport syndrome. Homology with retinal abnormalities seen in patients after surgical removal of the inner limiting membrane of the retina suggests that this is where the defect is located. We therefore suggest that the new retinal phenotypes and similar phenotypes can be described with the new definition "frail inner limiting membrane maculopathy." [ABSTRACT FROM AUTHOR]

Published
2024
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13. Is MED13L-related intellectual disability a recognizable syndrome?

Author

Tørring, Pernille Mathiesen, Larsen, Martin Jakob, Brasch-Andersen, Charlotte, Krogh, Lotte Nylandsted, Kibæk, Maria, Laulund, Lone, Illum, Niels, Dunkhase-Heinl, Ulrike, Wiesener, Antje, Popp, Bernt, Marangi, Giuseppe, Hjortshøj, Tina Duelund, Ek, Jakob, Vogel, Ida, Becher, Naja, Roos, Laura, Zollino, Marcella, and Fagerberg, Christina Ringmann

Published
2019
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14. Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes

Author

Lionel, Anath C, Tammimies, Kristiina, Vaags, Andrea K, Rosenfeld, Jill A, Ahn, Joo Wook, Merico, Daniele, Noor, Abdul, Runke, Cassandra K, Pillalamarri, Vamsee K, Carter, Melissa T, Gazzellone, Matthew J, Thiruvahindrapuram, Bhooma, Fagerberg, Christina, Laulund, Lone W, Pellecchia, Giovanna, Lamoureux, Sylvia, Deshpande, Charu, Clayton-Smith, Jill, White, Ann C, Leather, Susan, Trounce, John, Bedford, H Melanie, Hatchwell, Eli, Eis, Peggy S, Yuen, Ryan KC, Walker, Susan, Uddin, Mohammed, Geraghty, Michael T, Nikkel, Sarah M, Tomiak, Eva M, Fernandez, Bridget A, Soreni, Noam, Crosbie, Jennifer, Arnold, Paul D, Schachar, Russell J, Roberts, Wendy, Paterson, Andrew D, So, Joyce, Szatmari, Peter, Chrysler, Christina, Woodbury-Smith, Marc, Lowry, R Brian, Zwaigenbaum, Lonnie, Mandyam, Divya, Wei, John, MacDonald, Jeffrey R, Howe, Jennifer L, Nalpathamkalam, Thomas, Wang, Zhuozhi, Tolson, Daniel, Cobb, David S, Wilks, Timothy M, Sorensen, Mark J, Bader, Patricia I, An, Yu, Wu, Bai-Lin, Musumeci, Sebastiano Antonino, Romano, Corrado, Postorivo, Diana, Nardone, Anna M, Della Monica, Matteo, Scarano, Gioacchino, Zoccante, Leonardo, Novara, Francesca, Zuffardi, Orsetta, Ciccone, Roberto, Antona, Vincenzo, Carella, Massimo, Zelante, Leopoldo, Cavalli, Pietro, Poggiani, Carlo, Cavallari, Ugo, Argiropoulos, Bob, Chernos, Judy, Brasch-Andersen, Charlotte, Speevak, Marsha, Fichera, Marco, Ogilvie, Caroline Mackie, Shen, Yiping, Hodge, Jennelle C, Talkowski, Michael E, Stavropoulos, Dimitri J, Marshall, Christian R, and Scherer, Stephen W

Subjects
Pediatric Research Initiative, Pediatric, Intellectual and Developmental Disabilities (IDD), Mental Health, Brain Disorders, Human Genome, Neurosciences, Autism, Clinical Research, Behavioral and Social Science, Genetics, 2.1 Biological and endogenous factors, Aetiology, Mental health, Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Child, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, Pair 9, DNA Copy Number Variations, Exons, Female, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Glycoproteins, Humans, Infant, Infant, Newborn, Male, Nerve Tissue Proteins, Organ Specificity, Phenotype, Polymorphism, Single Nucleotide, Protein Isoforms, Receptors, Cell Surface, Risk Factors, Sequence Deletion, Transcription Factors, Transcription Initiation Site, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Young Adult, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Published
2014

15. Comprehensive Noninvasive Fetal Screening by Deep Trio-Exome Sequencing

Author

Miceikaitė, Ieva, primary, Hao, Qin, additional, Brasch-Andersen, Charlotte, additional, Fagerberg, Christina R., additional, Torring, Pernille M., additional, Kristiansen, Britta S., additional, Ousager, Lilian B., additional, Sperling, Lene, additional, Ibsen, Mette H., additional, Löser, Katrin, additional, and Larsen, Martin J., additional

Published
2023
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16. Generation of eight hiPSCs lines from two pathogenic variants in CACNA1A using the CRISPR-Cas9 gene editing technology

Author

Rivera-Sánchez, Paula, primary, Søndergaard, Line, additional, Wathikthinnakon, Methi, additional, B. D. Magnusson, Helena, additional, Frederiksen, Henriette R, additional, Aabæk Hammer, Freja, additional, Taleb, Reema, additional, Christian Cassidy, Conan, additional, Tranholm Bruun, Mads, additional, Tümer, Zeynep, additional, Holst, Bjørn, additional, Brasch-Andersen, Charlotte, additional, Møller, Rikke S, additional, Freude, Kristine, additional, and Chandrasekaran, Abinaya, additional

Published
2023
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18. Comprehensive prenatal diagnostics: Exome versus genome sequencing

Author

Miceikaite, Ieva, primary, Fagerberg, Christina, additional, Brasch‐Andersen, Charlotte, additional, Torring, Pernille Mathiesen, additional, Kristiansen, Britta Schlott, additional, Hao, Qin, additional, Sperling, Lene, additional, Ibsen, Mette Holm, additional, Löser, Katrin, additional, Bendsen, Eske Alf, additional, Ousager, Lilian Bomme, additional, and Larsen, Martin Jakob, additional

Published
2023
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19. Generation of eight hiPSCs lines from two pathogenic variants in CACNA1A using the CRISPR-Cas9 gene editing technology

Author

Rivera-Sánchez, Paula, Søndergaard, Line, Wathikthinnakon, Methi, B. D. Magnusson, Helena, Frederiksen, Henriette R., Aabæk Hammer, Freja, Taleb, Reema, Christian Cassidy, Conan, Tranholm Bruun, Mads, Tümer, Zeynep, Holst, Bjørn, Brasch-Andersen, Charlotte, Møller, Rikke, Freude, Kristine, Chandrasekaran, Abinaya, Rivera-Sánchez, Paula, Søndergaard, Line, Wathikthinnakon, Methi, B. D. Magnusson, Helena, Frederiksen, Henriette R., Aabæk Hammer, Freja, Taleb, Reema, Christian Cassidy, Conan, Tranholm Bruun, Mads, Tümer, Zeynep, Holst, Bjørn, Brasch-Andersen, Charlotte, Møller, Rikke, Freude, Kristine, and Chandrasekaran, Abinaya

Abstract

Developmental and epileptic encephalopathies (DEEs) are rare severe neurodevelopmental disorders with a cumulative incidence of 1:6.000 live births. Many epileptic conditions arise from single nucleotide variants in CACNA1A (calcium voltage-gated channel subunit alpha1 A), encoding the CaV2.1 calcium channel subunit. Human induced pluripotent stem cells (hiPSCs) are an optimal choice for modeling DEEs, as they can be differentiated in vitro into diverse neuronal subpopulations. Here, we report the generation of hiPSC lines with two pathogenic CACNA1A variants c.1767C > T, p. (Arg589Cys), referred to as R589C and c. 2139G > A, p.(Ala713Thr), referred to as A713T, previously associated with epilepsy. The variants were introduced into a hiPSC line from a healthy individual via CRISPR-Cas9 gene editing technology.

Published
2023

20. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

21. CUX1-related neurodevelopmental disorder:deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course., Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

23. Expansion of the neurodevelopmental phenotype of individuals with EEF1A2variants and genotype-phenotype study

Author

Paulet, Alix, Bennett-Ness, Cavan, Ageorges, Faustine, Trost, Detlef, Green, Andrew, Goudie, David, Jewell, Rosalyn, Kraatari-Tiri, Minna, PIARD, Juliette, Coubes, Christine, Lam, Wayne, Lynch, Sally Ann, Samuel, Groeschel, Ramond, Francis, Fluss, Joël, Fagerberg, Christina, Brasch Andersen, Charlotte, Varvagiannis, Konstantinos, Kleefstra, Tjitske, Gérard, Bénédicte, Fradin, Mélanie, Vitobello, Antonio, Tenconi, Romano, Denommé-Pichon, Anne-Sophie, Vincent-Devulder, Aline, Haack, Tobias, Marsh, Joseph A, Laulund, Lone Walentin, Grimmel, Mona, Riess, Angelika, de Boer, Elke, Padilla-Lopez, Sergio, Bakhtiari, Somayeh, Kruer, Michael C, Levy, Jonathan, Verloes, Alain, Abbott, Catherine M, and Ruaud, Lyse

Abstract

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.

Published
2024
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24. P159: Variants in cohesin release factors WAPL, PDS5A, and PDS5B define a new class of cohesinopathies*

Author

Boone, Philip, primary, Faour, Kamli, additional, Mohajeri, Kiana, additional, Lemanski, John, additional, Jana, Bimal, additional, Fu, Jack, additional, Kerkhof, Jennifer, additional, McConkey, Haley, additional, Collins, Ryan, additional, Lucente, Diane, additional, de Esch, Celine, additional, Moysés-Oliveira, Mariana, additional, Nuttle, Alexander, additional, Domingo, Aloysius, additional, Erdin, Serkan, additional, Hanley, Maris, additional, Watt, Amy, additional, Surette, Eric, additional, Lima, Gloria, additional, Smith, Laura, additional, Salani, Monica, additional, Yadav, Rachita, additional, Harripaul, Ricardo, additional, O’Keefe, Kathryn, additional, Burt, Nicholas, additional, Larson, Matthew, additional, Bhavsar, Riya, additional, Currall, Benjamin, additional, Sell, Susan, additional, Ladda, Roger, additional, Immken, LaDonna, additional, Buchanan, Catherine, additional, Yuan, Bo, additional, Lynch, Sally, additional, Gilissen, Christian, additional, Pfundt, Rolph, additional, Ockeloen, Charlotte, additional, Kleefstra, Tjitske, additional, Vanhoutte, Els, additional, Sinnema, Margje, additional, Stegmann, Sander, additional, Stevens, Servi, additional, Iascone, Maria, additional, Maitz, Silvia, additional, Cogne, Benjamin, additional, Le Caignec, Cedric, additional, Vincent, Marie, additional, Nizon, Mathilde, additional, Male, Alison, additional, Agrawal, Pankaj, additional, Thompson, Michelle, additional, Torring, Pernille, additional, Brasch-Andersen, Charlotte, additional, Faivre, Laurence, additional, Bruel, Ange-Line, additional, Isidor, Bertrand, additional, Philippe, Christophe, additional, Morleo, Manuela, additional, Wojcik, Monica, additional, Genetti, Casie, additional, Srivastava, Siddharth, additional, Ballal, Sonia, additional, Schließke, Sophia, additional, Jamra, Rami Abou, additional, Delahaye, Andree, additional, von Wintzingerode, Lydia, additional, Bothe, Viktoria, additional, Houlier, Marine, additional, Stout, Timothy, additional, Bergant, Gaber, additional, Peterlin, Borut, additional, Moldovan, Oana, additional, Martínez-Gil, Núria, additional, Argilli, Emanuela, additional, Sherr, Elliott, additional, Harel, Tamar, additional, Rosenberg-Fogler, Hallel, additional, Rosenfeld, Jill, additional, Wentzensen, Ingrid, additional, Westphal, Dominik, additional, Riedhammer, Korbinian, additional, Orec, Laura, additional, Gusella, James, additional, Sadikovic, Bekim, additional, Tai, Derek, additional, and Talkowski, Michael, additional

Published
2023
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25. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology

Author

Sobering, Andrew K., primary, Bryant, Laura M., additional, Li, Dong, additional, McGaughran, Julie, additional, Maystadt, Isabelle, additional, Moortgat, Stephanie, additional, Graham, John M., additional, van Haeringen, Arie, additional, Ruivenkamp, Claudia, additional, Cuperus, Roos, additional, Vogt, Julie, additional, Morton, Jenny, additional, Brasch-Andersen, Charlotte, additional, Steenhof, Maria, additional, Hansen, Lars Kjærsgaard, additional, Adler, Élodie, additional, Lyonnet, Stanislas, additional, Pingault, Veronique, additional, Sandrine, Marlin, additional, Ziegler, Alban, additional, Donald, Tyhiesia, additional, Nelson, Beverly, additional, Holt, Brandon, additional, Petryna, Oleksandra, additional, Firth, Helen, additional, McWalter, Kirsty, additional, Zyskind, Jacob, additional, Telegrafi, Aida, additional, Juusola, Jane, additional, Person, Richard, additional, Bamshad, Michael J., additional, Earl, Dawn, additional, Chun-Hui Tsai, Anne, additional, Yearwood, Katherine R., additional, Marco, Elysa, additional, Nowak, Catherine, additional, Douglas, Jessica, additional, Hakonarson, Hakon, additional, and Bhoj, Elizabeth J., additional

Published
2023
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26. CUX1-related neurodevelopmental disorder: Deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, primary, Marcos-Grañeda, Elia, additional, Weiss, Linnea, additional, Gurnett, Christina, additional, Jelsig, Anne Marie, additional, Vineke, Susanne, additional, Isidor, Bertrand, additional, Mercier, Sandra, additional, Magnussen, Kari, additional, Zacher, Pia, additional, Hashim, Mona, additional, Pagnamenta, Alistair, additional, Race, Simone, additional, Srivast, Siddharth, additional, Frazier, Zoë, additional, Maiwald, Robert, additional, Pergande, Matthias, additional, Milani, Donatella, additional, Rinelli, Martina, additional, Levy, Jonathan, additional, Krey, Ilona, additional, Fontana, Paolo, additional, Lonardo, Fortunato, additional, Riley, Stephanie, additional, Kretzer, Jasmine, additional, Rankin, Julia, additional, Reis, Linda, additional, Semina, Elena, additional, Reuter, Miriam, additional, Scherer, Stephen, additional, Iascone, Maria, additional, Weis, Denisa, additional, Fagerberg, Christina, additional, Brasch-Andersen, Charlotte, additional, Hansen, Lars, additional, Kuechler, Alma, additional, Noble, Nathan, additional, Gardham, Alice, additional, Tenney, Jessica, additional, Rathore, Geetanjali, additional, Beck-Woedl, Stefanie, additional, Haack, Tobias, additional, Pavlidou, Despina, additional, Atallah, Isis, additional, Vodopiutz, Julia, additional, Janecke, Andreas, additional, Lemke, Johannes, additional, Jamra, Rami Abou, additional, Nieto, Marta, additional, Tümer, Zeynep, additional, and Platzer, Konrad, additional

Published
2022
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28. Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder

Author

Cuinat, Silvestre, primary, Nizon, Mathilde, additional, Isidor, Bertrand, additional, Stegmann, Alexander, additional, van Jaarsveld, Richard H., additional, van Gassen, Koen L., additional, van der Smagt, Jasper J., additional, Volker-Touw, Catharina M.L., additional, Holwerda, Sjoerd J.B., additional, Terhal, Paulien A., additional, Schuhmann, Sarah, additional, Vasileiou, Georgia, additional, Khalifa, Mohamed, additional, Nugud, Alaa A., additional, Yasaei, Hemad, additional, Ousager, Lilian Bomme, additional, Brasch-Andersen, Charlotte, additional, Deb, Wallid, additional, Besnard, Thomas, additional, Simon, Marleen E.H., additional, Amsterdam, Karin Huijsdens-van, additional, Verbeek, Nienke E., additional, Matalon, Dena, additional, Dykzeul, Natalie, additional, White, Shana, additional, Spiteri, Elizabeth, additional, Devriendt, Koen, additional, Boogaerts, Anneleen, additional, Willemsen, Marjolein, additional, Brunner, Han G., additional, Sinnema, Margje, additional, De Vries, Bert B.A., additional, Gerkes, Erica H., additional, Pfundt, Rolph, additional, Izumi, Kosuke, additional, Krantz, Ian D., additional, Xu, Zhou L., additional, Murrell, Jill R., additional, Valenzuela, Irene, additional, Cusco, Ivon, additional, Rovira-Moreno, Eulàlia, additional, Yang, Yaping, additional, Bizaoui, Varoona, additional, Patat, Olivier, additional, Faivre, Laurence, additional, Tran-Mau-Them, Frederic, additional, Vitobello, Antonio, additional, Denommé-Pichon, Anne-Sophie, additional, Philippe, Christophe, additional, Bezieau, Stéphane, additional, and Cogné, Benjamin, additional

Published
2022
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29. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology

Author

Sobering, Andrew K., primary, Bryant, Laura M., additional, Li, Dong, additional, McGaughran, Julie, additional, Maystadt, Isabelle, additional, Moortgat, Stephanie, additional, Graham, John M., additional, van Haeringen, Arie, additional, Ruivenkamp, Claudia, additional, Cuperus, Roos, additional, Vogt, Julie, additional, Morton, Jenny, additional, Brasch-Andersen, Charlotte, additional, Steenhof, Maria, additional, Hansen, Lars Kjærsgaard, additional, Adler, Élodie, additional, Lyonnet, Stanislas, additional, Pingault, Veronique, additional, Sandrine, Marlin, additional, Ziegler, Alban, additional, Donald, Tyhiesia, additional, Nelson, Beverly, additional, Holt, Brandon, additional, Petryna, Oleksandra, additional, Firth, Helen, additional, McWalter, Kirsty, additional, Zyskind, Jacob, additional, Telegrafi, Aida, additional, Juusola, Jane, additional, Person, Richard, additional, Bamshad, Michael J., additional, Earl, Dawn, additional, Tsai, Anne Chun-Hui, additional, Yearwood, Katherine R., additional, Marco, Elysa, additional, Nowak, Catherine, additional, Douglas, Jessica, additional, Hakonarson, Hakon, additional, and Bhoj, Elizabeth J., additional

Published
2022
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30. Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder

Author

Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Circulatory Health, Cuinat, Silvestre, Nizon, Mathilde, Isidor, Bertrand, Stegmann, Alexander, van Jaarsveld, Richard H, van Gassen, Koen L, van der Smagt, Jasper J, Volker-Touw, Catharina M L, Holwerda, Sjoerd J B, Terhal, Paulien A, Schuhmann, Sarah, Vasileiou, Georgia, Khalifa, Mohamed, Nugud, Alaa A, Yasaei, Hemad, Ousager, Lilian Bomme, Brasch-Andersen, Charlotte, Deb, Wallid, Besnard, Thomas, Simon, Marleen E H, Amsterdam, Karin Huijsdens-van, Verbeek, Nienke E, Matalon, Dena, Dykzeul, Natalie, White, Shana, Spiteri, Elizabeth, Devriendt, Koen, Boogaerts, Anneleen, Willemsen, Marjolein, Brunner, Han G, Sinnema, Margje, De Vries, Bert B A, Gerkes, Erica H, Pfundt, Rolph, Izumi, Kosuke, Krantz, Ian D, Xu, Zhou L, Murrell, Jill R, Valenzuela, Irene, Cusco, Ivon, Rovira-Moreno, Eulàlia, Yang, Yaping, Bizaoui, Varoona, Patat, Olivier, Faivre, Laurence, Tran-Mau-Them, Frederic, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Philippe, Christophe, Bezieau, Stéphane, Cogné, Benjamin, Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Circulatory Health, Cuinat, Silvestre, Nizon, Mathilde, Isidor, Bertrand, Stegmann, Alexander, van Jaarsveld, Richard H, van Gassen, Koen L, van der Smagt, Jasper J, Volker-Touw, Catharina M L, Holwerda, Sjoerd J B, Terhal, Paulien A, Schuhmann, Sarah, Vasileiou, Georgia, Khalifa, Mohamed, Nugud, Alaa A, Yasaei, Hemad, Ousager, Lilian Bomme, Brasch-Andersen, Charlotte, Deb, Wallid, Besnard, Thomas, Simon, Marleen E H, Amsterdam, Karin Huijsdens-van, Verbeek, Nienke E, Matalon, Dena, Dykzeul, Natalie, White, Shana, Spiteri, Elizabeth, Devriendt, Koen, Boogaerts, Anneleen, Willemsen, Marjolein, Brunner, Han G, Sinnema, Margje, De Vries, Bert B A, Gerkes, Erica H, Pfundt, Rolph, Izumi, Kosuke, Krantz, Ian D, Xu, Zhou L, Murrell, Jill R, Valenzuela, Irene, Cusco, Ivon, Rovira-Moreno, Eulàlia, Yang, Yaping, Bizaoui, Varoona, Patat, Olivier, Faivre, Laurence, Tran-Mau-Them, Frederic, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Philippe, Christophe, Bezieau, Stéphane, and Cogné, Benjamin

Published
2022

33. Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans

Author

Qi, Cai, primary, Feng, Irena, additional, Costa, Ana Rita, additional, Pinto-Costa, Rita, additional, Neil, Jennifer E., additional, Caluseriu, Oana, additional, Li, Dong, additional, Ganetzky, Rebecca D., additional, Brasch-Andersen, Charlotte, additional, Fagerberg, Christina, additional, Hansen, Lars Kjærsgaard, additional, Bupp, Caleb, additional, Muraresku, Colleen Clarke, additional, Ruan, Xiangbin, additional, Kang, Bowei, additional, Hu, Kaining, additional, Zhong, Rong, additional, Brites, Pedro, additional, Bhoj, Elizabeth J., additional, Hill, Robert Sean, additional, Falk, Marni J., additional, Hakonarson, Hakon, additional, Kahle, Kristopher T., additional, Sousa, Monica M., additional, Walsh, Christopher A., additional, and Zhang, Xiaochang, additional

Published
2022
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34. Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring

Author

Nagy, Dóra, primary, Verheyen, Sarah, additional, Wigby, Kristen M., additional, Borovikov, Artem, additional, Sharkov, Artem, additional, Slegesky, Valerie, additional, Larson, Austin, additional, Fagerberg, Christina, additional, Brasch-Andersen, Charlotte, additional, Kibæk, Maria, additional, Bader, Ingrid, additional, Hernan, Rebecca, additional, High, Frances A., additional, Chung, Wendy K., additional, Schieving, Jolanda H., additional, Behunova, Jana, additional, Smogavec, Mateja, additional, Laccone, Franco, additional, Witsch-Baumgartner, Martina, additional, Zobel, Joachim, additional, Duba, Hans-Christoph, additional, and Weis, Denisa, additional

Published
2022
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38. ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder

Author

Oates, Stephanie, primary, Absoud, Michael, additional, Goyal, Sushma, additional, Bayley, Sophie, additional, Baulcomb, Jennifer, additional, Sims, Annemarie, additional, Riddett, Amy, additional, Allis, Katrina, additional, Brasch‐Andersen, Charlotte, additional, Balasubramanian, Meena, additional, Bai, Renkui, additional, Callewaert, Bert, additional, Hüffmeier, Ulrike, additional, Le Duc, Diana, additional, Radtke, Maximilian, additional, Korff, Christian, additional, Kennedy, Joanna, additional, Low, Karen, additional, Møller, Rikke S., additional, Nielsen, Jens Erik Klint, additional, Popp, Bernt, additional, Quteineh, Lina, additional, Rønde, Gitte, additional, Schönewolf‐Greulich, Bitten, additional, Shillington, Amelle, additional, Taylor, Matthew RG, additional, Todd, Emily, additional, Torring, Pernille M., additional, Tümer, Zeynep, additional, Vasileiou, Georgia, additional, Yates, T. Michael, additional, Zweier, Christiane, additional, Rosch, Richard, additional, Basson, M. Albert, additional, and Pal, Deb K., additional

Published
2021
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39. Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder

Author

Morava, Eva, primary, Schatz, Ulrich A., additional, Torring, Pernille M., additional, Abbott, Mary-Alice, additional, Baumann, Matthias, additional, Brasch-Andersen, Charlotte, additional, Chevalier, Nathalie, additional, Dunkhase-Heinl, Ulrike, additional, Fleger, Martin, additional, Haack, Tobias B., additional, Nelson, Stephen, additional, Potelle, Sven, additional, Radenkovic, Silvia, additional, Bommer, Guido T., additional, Van Schaftingen, Emile, additional, and Veiga-da-Cunha, Maria, additional

Published
2021
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40. Additional file 3 of Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Gillentine, Madelyn A., Tianyun Wang, Hoekzema, Kendra, Rosenfeld, Jill, Pengfei Liu, Guo, Hui, Kim, Chang N., De Vries, Bert B. A., Lisenka E. L. M. Vissers, Nordenskjold, Magnus, Kvarnung, Malin, Lindstrand, Anna, Nordgren, Ann, Gecz, Jozef, Iascone, Maria, Cereda, Anna, Scatigno, Agnese, Maitz, Silvia, Zanni, Ginevra, Bertini, Enrico, Zweier, Christiane, Schuhmann, Sarah, Wiesener, Antje, Pepper, Micah, Panjwani, Heena, Torti, Erin, Abid, Farida, Anselm, Irina, Siddharth Srivastava, Paldeep Atwal, Bacino, Carlos A., Gifty Bhat, Cobian, Katherine, Bird, Lynne M., Friedman, Jennifer, Wright, Meredith S., Callewaert, Bert, Petit, Florence, Mathieu, Sophie, Afenjar, Alexandra, Celenie K. Christensen, White, Kerry M., Elpeleg, Orly, Berger, Itai, Espineli, Edward J., Fagerberg, Christina, Brasch-Andersen, Charlotte, Hansen, Lars Kjærsgaard, Feyma, Timothy, Hughes, Susan, Thiffault, Isabelle, Sullivan, Bonnie, Yan, Shuang, Keller, Kory, Keren, Boris, Mignot, Cyril, Kooy, Frank, Meuwissen, Marije, Basinger, Alice, Kukolich, Mary, Philips, Meredith, Ortega, Lucia, Drummond-Borg, Margaret, Lauridsen, Mathilde, Sorensen, Kristina, Lehman, Anna, Lopez-Rangel, Elena, Levy, Paul, Lessel, Davor, Lotze, Timothy, Suneeta Madan-Khetarpal, Sebastian, Jessica, Vento, Jodie, Vats, Divya, L. Manace Benman, Mckee, Shane, Ghayda M. Mirzaa, Muss, Candace, Pappas, John, Peeters, Hilde, Romano, Corrado, Elia, Maurizio, Galesi, Ornella, Simon, Marleen E. H., Van Gassen, Koen L. I., Simpson, Kara, Stratton, Robert, Sabeen Syed, Thevenon, Julien, Palafoll, Irene Valenzuela, Vitobello, Antonio, Bournez, Marie, Faivre, Laurence, Xia, Kun, Earl, Rachel K., Nowakowski, Tomasz, Bernier, Raphael A., and Eichler, Evan E.

Subjects
Data_FILES
Abstract

Additional file 3: Table S13. GenBank accession numbers.

Published
2021
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41. Additional file 2 of Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Gillentine, Madelyn A., Tianyun Wang, Hoekzema, Kendra, Rosenfeld, Jill, Pengfei Liu, Guo, Hui, Kim, Chang N., De Vries, Bert B. A., Lisenka E. L. M. Vissers, Nordenskjold, Magnus, Kvarnung, Malin, Lindstrand, Anna, Nordgren, Ann, Gecz, Jozef, Iascone, Maria, Cereda, Anna, Scatigno, Agnese, Maitz, Silvia, Zanni, Ginevra, Bertini, Enrico, Zweier, Christiane, Schuhmann, Sarah, Wiesener, Antje, Pepper, Micah, Panjwani, Heena, Torti, Erin, Abid, Farida, Anselm, Irina, Siddharth Srivastava, Paldeep Atwal, Bacino, Carlos A., Gifty Bhat, Cobian, Katherine, Bird, Lynne M., Friedman, Jennifer, Wright, Meredith S., Callewaert, Bert, Petit, Florence, Mathieu, Sophie, Afenjar, Alexandra, Celenie K. Christensen, White, Kerry M., Elpeleg, Orly, Berger, Itai, Espineli, Edward J., Fagerberg, Christina, Brasch-Andersen, Charlotte, Hansen, Lars Kjærsgaard, Feyma, Timothy, Hughes, Susan, Thiffault, Isabelle, Sullivan, Bonnie, Yan, Shuang, Keller, Kory, Keren, Boris, Mignot, Cyril, Kooy, Frank, Meuwissen, Marije, Basinger, Alice, Kukolich, Mary, Philips, Meredith, Ortega, Lucia, Drummond-Borg, Margaret, Lauridsen, Mathilde, Sorensen, Kristina, Lehman, Anna, Lopez-Rangel, Elena, Levy, Paul, Lessel, Davor, Lotze, Timothy, Suneeta Madan-Khetarpal, Sebastian, Jessica, Vento, Jodie, Vats, Divya, L. Manace Benman, Mckee, Shane, Ghayda M. Mirzaa, Muss, Candace, Pappas, John, Peeters, Hilde, Romano, Corrado, Elia, Maurizio, Galesi, Ornella, Simon, Marleen E. H., Van Gassen, Koen L. I., Simpson, Kara, Stratton, Robert, Sabeen Syed, Thevenon, Julien, Palafoll, Irene Valenzuela, Vitobello, Antonio, Bournez, Marie, Faivre, Laurence, Xia, Kun, Earl, Rachel K., Nowakowski, Tomasz, Bernier, Raphael A., and Eichler, Evan E.

Abstract

Additional file 2: Supplementary Figures S1-S5. Fig. S1. Dendrogram of hnRNPs based on multiple sequence alignment of canonical amino acid sequences. Colors match those seen in Fig. 2. NDD hnRNPs are shown in black boxes. Fig. S2. Pathogenicity assessment of variation in hnRNPs. A) Gene Variation Intolerance Ranking (GeVIR), loss-of-function observed/expected upper bound fraction (LOEUF), and Variation Intolerant Region Loss-of-Function (VIRLoF) percentiles. Average LOEUF percentile is significantly higher for NDD HNRNPs (n = 13) compared to other HNRNPs (n = 15). B) Average fold change for GeVIR, LEOUF, and VIRLoF for autosomal dominant (AD) and autosomal recessive (AR) variants. Average LEOUF fold change for AD mutations is significantly higher for NDD HNRNPs compared to other HNRNPs, with the AD VIRLoF fold change trending in the same direction. The AR LEOUF fold change is trending towards being significantly higher among other HNRNPs compared to NDD HNRNPs. One-way t-test. * p

Published
2021
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42. ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder

Author

Oates, Stephanie, Absoud, Michael, Goyal, Sushma, Bayley, Sophie, Baulcomb, Jennifer, Sims, Annemarie, Riddett, Amy, Allis, Katrina, Brasch-Andersen, Charlotte, Balasubramanian, Meena, Bai, Renkui, Callewaert, Bert, Hüffmeier, Ulrike, Le Duc, Diana, Radtke, Maximilian, Korff, Christian, Kennedy, Joanna, Low, Karen, Møller, Rikke S., Nielsen, Jens Erik Klint, Popp, Bernt, Quteineh, Lina, Rønde, Gitte, Schönewolf-Greulich, Bitten, Shillington, Amelle, Taylor, Matthew R.G., Todd, Emily, Torring, Pernille M., DMSc, Zeynep Tümer M.D.Ph D., Vasileiou, Georgia, Yates, T. Michael, Zweier, Christiane, Rosch, Richard, Basson, M. Albert, Pal, Deb K., Oates, Stephanie, Absoud, Michael, Goyal, Sushma, Bayley, Sophie, Baulcomb, Jennifer, Sims, Annemarie, Riddett, Amy, Allis, Katrina, Brasch-Andersen, Charlotte, Balasubramanian, Meena, Bai, Renkui, Callewaert, Bert, Hüffmeier, Ulrike, Le Duc, Diana, Radtke, Maximilian, Korff, Christian, Kennedy, Joanna, Low, Karen, Møller, Rikke S., Nielsen, Jens Erik Klint, Popp, Bernt, Quteineh, Lina, Rønde, Gitte, Schönewolf-Greulich, Bitten, Shillington, Amelle, Taylor, Matthew R.G., Todd, Emily, Torring, Pernille M., DMSc, Zeynep Tümer M.D.Ph D., Vasileiou, Georgia, Yates, T. Michael, Zweier, Christiane, Rosch, Richard, Basson, M. Albert, and Pal, Deb K.

Abstract

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype–phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype–phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.

Published
2021

43. National data on the early clinical use of non-invasive prenatal testing in public and private healthcare in Denmark 2013–2017

Author

Lund, Ida C.B., Petersen, Olav B., Becher, Naja H., Lildballe, Dorte L., Jørgensen, Finn S., Ambye, Louise, Skibsted, Lillian, Ernst, Anja, Jensen, Ann N., Fagerberg, Christina, Brasch-Andersen, Charlotte, Tabor, Ann, Zingenberg, Helle J., Nørgaard, Pernille, Almind, Gitte J., Vestergaard, Else Marie, Vogel, Ida, Lund, Ida C.B., Petersen, Olav B., Becher, Naja H., Lildballe, Dorte L., Jørgensen, Finn S., Ambye, Louise, Skibsted, Lillian, Ernst, Anja, Jensen, Ann N., Fagerberg, Christina, Brasch-Andersen, Charlotte, Tabor, Ann, Zingenberg, Helle J., Nørgaard, Pernille, Almind, Gitte J., Vestergaard, Else Marie, and Vogel, Ida

Abstract

Introduction: In Denmark, non-invasive prenatal testing (NIPT) has been used since 2013. We aimed to evaluate the early clinical use of NIPT in Danish public and private healthcare settings before NIPT became an integrated part of the national guidelines on prenatal screening and diagnosis in 2017. Material and methods: NIPT data were collected between March 2013 and June 2017 from national public registries and private providers. Results from follow-up samples (chorionic villi, amniotic fluid, postnatal blood or fetal tissue) were included from The Danish Cytogenetics Central Registry and indications and outcome from The Danish Fetal Medicine Database. Results: A total of 3936 NIPT results were included in the study from public hospitals (n = 3463, 88.0%) and private clinics (n = 473, 12.0%). The total number of prenatal tests was 19 713 during the study period: 20% were NIPT analyses (n = 3936) and 80% invasive procedures (n = 15 777). Twenty-five percent of NIPTs in the private clinics were performed before gestational week 11+0, whereas NIPT in public settings was used only after combined first trimester screening (P <.001). Regardless of indication, the national public sensitivity was 96.9% (95% CI 82.0%-99.8%) for trisomy 21, 100% (95% CI 46.3%-100%) for trisomy 18, 100% (95% CI 5.5%-100%) for trisomy 13, and 87.0% (95% CI 74.5%-92.4%) for any fetal chromosomal aberration. Forty-seven true-positive NIPT results included cases of common aneuplodies (trisomy 21, n = 31; trisomy 18, n = 5; and trisomy 13, n = 1), sex chromosomal aberrations (n = 7) and atypical chromosomal aberrations (n = 3). One false-negative NIPT result occurred (trisomy 21). Of 47 cases, 21 (45%) cases with a true-positive NIPT result resulted in live births by choice; 11 of these children had Down and 4 had Edwards syndrome. Conclusions: The total number of NIPT analyses was low compared with the number of invasive procedures in the implementation period. In contrast to the

Published
2021

44. Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome:Five Danish patients with novel variants in AHDC1

Author

Faergeman, Soren L., Bojesen, Anders B., Rasmussen, Maria, Becher, Naja, Andreasen, Lotte, Andersen, Brian N., Erbs, Emilie, Lildballe, Dorte L., Nielsen, Jens Erik K., Zilmer, Monica, Hammer, Trine Bjørg, Andersen, Mikkel, Brasch-Andersen, Charlotte, Fagerberg, Christina R., Illum, Niels O., Thorup, Mette B., Gregersen, Pernille A., Faergeman, Soren L., Bojesen, Anders B., Rasmussen, Maria, Becher, Naja, Andreasen, Lotte, Andersen, Brian N., Erbs, Emilie, Lildballe, Dorte L., Nielsen, Jens Erik K., Zilmer, Monica, Hammer, Trine Bjørg, Andersen, Mikkel, Brasch-Andersen, Charlotte, Fagerberg, Christina R., Illum, Niels O., Thorup, Mette B., and Gregersen, Pernille A.

Abstract

Xia-Gibbs syndrome (XGS) is a neurodevelopmental disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, obstructive sleep apnoea and mild facial dysmorphism. Heterozygosity for loss-of-function variants in AHDC1, encoding the AT-hook DNA binding motif containing protein 1, were discovered in 2014 as the likely genetic cause of Xia-Gibbs syndrome. We present five patients with Xia-Gibbs syndrome caused by previously unreported variants in AHDC1. Two of the patients share a frameshift variant: c.2849del (p.(Pro950Argfs*192)) in AHDC1. Despite sharing this variant, the two patients show remarkable phenotypic differences underscoring the clinical heterogeneity of Xia-Gibbs syndrome. In addition, we present a case of Xia-Gibbs syndrome caused by mosaicism for an AHDC1 variant.

Published
2021

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