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1. The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations.

Author

van Bon, Bregje, Brooks, Alice, Guan, Qiaoning, Klee, Eric, Marcelis, Carlo, Rosado, Joel, Schimmenti, Lisa, Shikany, Amy, Terhal, Paulien, Nicole Weaver, Kathryn, Wessels, Marja, van Wieringen, Hester, Hurst, Anna, Gooch, Catherine, Steindl, Katharina, Joset, Pascal, Rauch, Anita, Tartaglia, Marco, Niceta, Marcello, Elgersma, Ype, Demirdas, Serwet, van Woerden, Geeske, Senden, Richelle, de Konink, Charlotte, Trezza, Rossella, Baban, Anwar, Bassetti, Jennifer, van Bever, Yolande, and Bird, Lynne

Subjects
MAP3K7, Noonan syndrome, cardiospondylocarpofacial syndrome, frontometaphyseal dysplasia type 2, Abnormalities, Multiple, Genotype, Hearing Loss, Bilateral, Humans, Mitral Valve Insufficiency, Mutation, Noonan Syndrome, Osteosclerosis, Phenotype
Abstract

Mitogen-activated protein 3 kinase 7 (MAP3K7) encodes the ubiquitously expressed transforming growth factor β-activated kinase 1, which plays a crucial role in many cellular processes. Mutationsin the MAP3K7 gene have been linked to two distinct disorders: frontometaphyseal dysplasia type 2 (FMD2) and cardiospondylocarpofacial syndrome (CSCF). The fact that different mutations can induce two distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here, we significantly expand the cohort and the description of clinical phenotypes for patients with CSCF and FMD2 who carry mutations in MAP3K7. Our findings support that in contrast to FMD2-causing mutations, CSCF-causing mutations in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic mutations in MAP3K7 are at risk for (severe) cardiac disease, have symptoms associated with connective tissue disease, and we show overlap in clinical phenotypes of CSCF with Noonan syndrome (NS). Together, we confirm a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 mutations and conclude that mutations in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders, and in the differential diagnosis of NS.

Published
2022

2. Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling

Author

Boonsawat, Paranchai, Asadollahi, Reza, Niedrist, Dunja, Steindl, Katharina, Begemann, Anaïs, Joset, Pascal, Bhoj, Elizabeth J., Li, Dong, Zackai, Elaine, Vetro, Annalisa, Barba, Carmen, Guerrini, Renzo, Whalen, Sandra, Keren, Boris, Khan, Amjad, Jing, Duan, Palomares Bralo, María, Rikeros Orozco, Emi, Hao, Qin, Schlott Kristiansen, Britta, Zheng, Bixia, Donnelly, Deirdre, Clowes, Virginia, Zweier, Markus, Papik, Michael, Siegel, Gabriele, Sabatino, Valeria, Mocera, Martina, Horn, Anselm H.C., Sticht, Heinrich, and Rauch, Anita

Published
2024
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5. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Author

Johnson, Brett V, Kumar, Raman, Oishi, Sabrina, Alexander, Suzy, Kasherman, Maria, Vega, Michelle Sanchez, Ivancevic, Atma, Gardner, Alison, Domingo, Deepti, Corbett, Mark, Parnell, Euan, Yoon, Sehyoun, Oh, Tracey, Lines, Matthew, Lefroy, Henrietta, Kini, Usha, Van Allen, Margot, Grønborg, Sabine, Mercier, Sandra, Küry, Sébastien, Bézieau, Stéphane, Pasquier, Laurent, Raynaud, Martine, Afenjar, Alexandra, Billette de Villemeur, Thierry, Keren, Boris, Désir, Julie, Van Maldergem, Lionel, Marangoni, Martina, Dikow, Nicola, Koolen, David A, VanHasselt, Peter M, Weiss, Marjan, Zwijnenburg, Petra, Sa, Joaquim, Reis, Claudia Falcao, López-Otín, Carlos, Santiago-Fernández, Olaya, Fernández-Jaén, Alberto, Rauch, Anita, Steindl, Katharina, Joset, Pascal, Goldstein, Amy, Madan-Khetarpal, Suneeta, Infante, Elena, Zackai, Elaine, Mcdougall, Carey, Narayanan, Vinodh, Ramsey, Keri, Mercimek-Andrews, Saadet, Pena, Loren, Shashi, Vandana, Undiagnosed Diseases Network, Schoch, Kelly, Sullivan, Jennifer A, Pinto E Vairo, Filippo, Pichurin, Pavel N, Ewing, Sarah A, Barnett, Sarah S, Klee, Eric W, Perry, M Scott, Koenig, Mary Kay, Keegan, Catherine E, Schuette, Jane L, Asher, Stephanie, Perilla-Young, Yezmin, Smith, Laurie D, Rosenfeld, Jill A, Bhoj, Elizabeth, Kaplan, Paige, Li, Dong, Oegema, Renske, van Binsbergen, Ellen, van der Zwaag, Bert, Smeland, Marie Falkenberg, Cutcutache, Ioana, Page, Matthew, Armstrong, Martin, Lin, Angela E, Steeves, Marcie A, Hollander, Nicolette den, Hoffer, Mariëtte JV, Reijnders, Margot RF, Demirdas, Serwet, Koboldt, Daniel C, Bartholomew, Dennis, Mosher, Theresa Mihalic, Hickey, Scott E, Shieh, Christine, Sanchez-Lara, Pedro A, Graham, John M, Tezcan, Kamer, Schaefer, GB, Danylchuk, Noelle R, Asamoah, Alexander, Jackson, Kelly E, Yachelevich, Naomi, Au, Margaret, Pérez-Jurado, Luis A, and Kleefstra, Tjitske

Subjects
Undiagnosed Diseases Network, Animals, Humans, Mice, Ubiquitin Thiolesterase, Transforming Growth Factor beta, Developmental Disabilities, Signal Transduction, Phenotype, Female, Male, Haploinsufficiency, Intellectual Disability, Brain malformation, Deubiquitylating enzyme, Hippocampus, Neurodevelopmental disorder, TGFβ, USP9X, Congenital Structural Anomalies, Genetics, Neurosciences, Pediatric, Mental Health, Behavioral and Social Science, Brain Disorders, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, TGF beta, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundThe X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.MethodsWe used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.ResultsTwelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.ConclusionsOur data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

Published
2020

6. De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects

Author

Accogli, Andrea, Calabretta, Sara, St-Onge, Judith, Boudrahem-Addour, Nassima, Dionne-Laporte, Alexandre, Joset, Pascal, Azzarello-Burri, Silvia, Rauch, Anita, Krier, Joel, Fieg, Elizabeth, Pallais, Juan C, Network, Undiagnosed Diseases, Acosta, Maria T, Adams, David R, Agrawal, Pankaj, Alejandro, Mercedes E, Allard, Patrick, Alvey, Justin, Andrews, Ashley, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Barbouth, Deborah, Batzli, Gabriel F, Bayrak-Toydemir, Pinar, Beggs, Alan H, Bejerano, Gill, Bellen, Hugo J, Bernstein, Jonathan A, Berry, Gerard T, Bican, Anna, Bick, David P, Birch, Camille L, Bivona, Stephanie, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Boone, Braden E, Bostwick, Bret L, Botto, Lorenzo, Briere, Lauren C, Brokamp, Elly, Brown, Donna M, Brush, Matthew, Burke, Elizabeth A, Burrage, Lindsay C, Butte, Manish J, Carey, John, Carrasquillo, Olveen, Chang, Ta Chen Peter, Chao, Hsiao-Tuan, Clark, Gary D, Coakley, Terra R, Cobban, Laurel A, Cogan, Joy D, Cole, F Sessions, Colley, Heather A, Cooper, Cynthia M, Cope, Heidi, Craigen, William J, D’Souza, Precilla, Dasari, Surendra, Davids, Mariska, Dayal, Jyoti G, Dell’Angelica, Esteban C, Dhar, Shweta U, Dorrani, Naghmeh, Dorset, Daniel C, Douine, Emilie D, Draper, David D, Duncan, Laura, Eckstein, David J, Emrick, Lisa T, Eng, Christine M, Esteves, Cecilia, Estwick, Tyra, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L, Fisher, Paul G, Fogel, Brent L, Forghani, Irman, Fresard, Laure, Gahl, William A, Godfrey, Rena A, Goldman, Alica M, Goldstein, David B, Gourdine, Jean-Philippe F, Grajewski, Alana, Groden, Catherine A, Gropman, Andrea L, Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A, and Hayes, Nichole

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Axons, Cadherins, Corpus Callosum, Eye, Frameshift Mutation, Genitalia, Heart Defects, Congenital, Heterozygote, Humans, Neurodevelopmental Disorders, Undiagnosed Diseases Network, ACOG, CDH2, N-cadherin, cardiac defects, cell-cell adhesion, corpus callosum, eye defects, genital defects, intellectual disability, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

Published
2019

8. Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Author

Škorić-Milosavljević, Doris, Lahrouchi, Najim, Bosada, Fernanda M., Dombrowsky, Gregor, Williams, Simon G., Lesurf, Robert, Tjong, Fleur V.Y., Walsh, Roddy, El Bouchikhi, Ihssane, Breckpot, Jeroen, Audain, Enrique, Ilgun, Aho, Beekman, Leander, Ratbi, Ilham, Strong, Alanna, Muenke, Maximilian, Heide, Solveig, Muir, Alison M., Hababa, Mariam, Cross, Laura, Zhou, Dihong, Pastinen, Tomi, Hitz, Marc-Phillip, Abdul-Khaliq, Hashim, Berger, Felix, Dähnert, Ingo, Dittrich, Sven, Uebing, Anselm, Stiller, Brigitte, Zackai, Elaine, Atmani, Samir, Ouldim, Karim, Adadi, Najlae, Steindl, Katharina, Rauch, Anita, Brook, David, Wilsdon, Anna, Kuipers, Irene, Blom, Nico A., Mulder, Barbara J., Mefford, Heather C., Keren, Boris, Joset, Pascal, Kruszka, Paul, Thiffault, Isabelle, Sheppard, Sarah E., Roberts, Amy, Lodder, Elisabeth M., Keavney, Bernard D., Clur, Sally-Ann B., Mital, Seema, Hitz, Marc-Philip, Christoffels, Vincent M., Postma, Alex V., and Bezzina, Connie R.

Published
2021
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9. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Author

Zanoni, Paolo, Steindl, Katharina, Sengupta, Deepanwita, Joset, Pascal, Bahr, Angela, Sticht, Heinrich, Lang-Muritano, Mariarosaria, van Ravenswaaij-Arts, Conny M. A., Shinawi, Marwan, Andrews, Marisa, Attie-Bitach, Tania, Maystadt, Isabelle, Belnap, Newell, Benoit, Valerie, Delplancq, Geoffroy, de Vries, Bert B. A., Grotto, Sarah, Lacombe, Didier, Larson, Austin, Mourmans, Jeroen, Õunap, Katrin, Petrilli, Giulia, Pfundt, Rolph, Ramsey, Keri, Blok, Lot Snijders, Tsatsaris, Vassilis, Vitobello, Antonio, Faivre, Laurence, Wheeler, Patricia G., Wevers, Marijke R., Wojcik, Monica, Zweier, Markus, Gozani, Or, and Rauch, Anita

Published
2021
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10. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Author

Kummeling, Joost, Stremmelaar, Diante E., Raun, Nicholas, Reijnders, Margot R. F., Willemsen, Marjolein H., Ruiterkamp-Versteeg, Martina, Schepens, Marga, Man, Calvin C. O., Gilissen, Christian, Cho, Megan T., McWalter, Kirsty, Sinnema, Margje, Wheless, James W., Simon, Marleen E. H., Genetti, Casie A., Casey, Alicia M., Terhal, Paulien A., van der Smagt, Jasper J., van Gassen, Koen L. I., Joset, Pascal, Bahr, Angela, Steindl, Katharina, Rauch, Anita, Keller, Elmar, Raas-Rothschild, Annick, Koolen, David A., Agrawal, Pankaj B., Hoffman, Trevor L., Powell-Hamilton, Nina N., Thiffault, Isabelle, Engleman, Kendra, Zhou, Dihong, Bodamer, Olaf, Hoefele, Julia, Riedhammer, Korbinian M., Schwaibold, Eva M. C., Tasic, Velibor, Schubert, Dirk, Top, Deniz, Pfundt, Rolph, Higgs, Martin R., Kramer, Jamie M., and Kleefstra, Tjitske

Published
2021
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12. SwissGenVar: A Platform for Clinical-Grade Interpretation of Genetic Variants to Foster Personalized Healthcare in Switzerland

Author

Kraemer, Dennis; https://orcid.org/0000-0001-7084-2068, Terumalai, Dillenn, Famiglietti, Maria Livia; https://orcid.org/0000-0002-5283-6593, Filges, Isabel; https://orcid.org/0000-0002-2149-6354, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Koller, Samuel; https://orcid.org/0000-0003-0965-0539, Maurer, Fabienne; https://orcid.org/0000-0002-6837-5963, Meier, Stéphanie, Nouspikel, Thierry; https://orcid.org/0000-0002-6650-9147, Sanz, Javier; https://orcid.org/0000-0001-6386-0313, Zweier, Christiane; https://orcid.org/0000-0001-8002-2020, Abramowicz, Marc; https://orcid.org/0000-0003-0623-8768, Berger, Wolfgang; https://orcid.org/0000-0002-0370-3815, Cichon, Sven; https://orcid.org/0000-0002-9475-086X, Schaller, André; https://orcid.org/0000-0001-5174-5764, Superti-Furga, Andrea; https://orcid.org/0000-0002-3543-7531, Barbié, Valérie; https://orcid.org/0009-0006-8085-9393, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Kraemer, Dennis; https://orcid.org/0000-0001-7084-2068, Terumalai, Dillenn, Famiglietti, Maria Livia; https://orcid.org/0000-0002-5283-6593, Filges, Isabel; https://orcid.org/0000-0002-2149-6354, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Koller, Samuel; https://orcid.org/0000-0003-0965-0539, Maurer, Fabienne; https://orcid.org/0000-0002-6837-5963, Meier, Stéphanie, Nouspikel, Thierry; https://orcid.org/0000-0002-6650-9147, Sanz, Javier; https://orcid.org/0000-0001-6386-0313, Zweier, Christiane; https://orcid.org/0000-0001-8002-2020, Abramowicz, Marc; https://orcid.org/0000-0003-0623-8768, Berger, Wolfgang; https://orcid.org/0000-0002-0370-3815, Cichon, Sven; https://orcid.org/0000-0002-9475-086X, Schaller, André; https://orcid.org/0000-0001-5174-5764, Superti-Furga, Andrea; https://orcid.org/0000-0002-3543-7531, Barbié, Valérie; https://orcid.org/0009-0006-8085-9393, and Rauch, Anita; https://orcid.org/0000-0003-2930-3163

Abstract

Large-scale next-generation sequencing (NGS) germline testing is technically feasible today, but variant interpretation represents a major bottleneck in analysis workflows. This includes extensive variant prioritization, annotation, and time-consuming evidence curation. The scale of the interpretation problem is massive, and variants of uncertain significance (VUSs) are a challenge to personalized medicine. This challenge is further compounded by the complexity and heterogeneity of the standards used to describe genetic variants and the associated phenotypes when searching for relevant information to support clinical decision making. To address this, all five Swiss academic institutions for Medical Genetics joined forces with the Swiss Institute of Bioinformatics (SIB) to create SwissGenVar as a user-friendly nationwide repository and sharing platform for genetic variant data generated during routine diagnostic procedures and research sequencing projects. Its aim is to provide a protected environment for expert evidence sharing about individual variants to harmonize and upscale their significance interpretation at the clinical grade according to international standards. To corroborate the clinical assessment, the variant-related data will be combined with consented high-quality clinical information. Broader visibility will be achieved by interfacing with international databases, thus supporting global initiatives in personalized healthcare.

Published
2024

13. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Author

Lenaerts, Lisa, Reynhout, Sara, Verbinnen, Iris, Laumonnier, Frédéric, Toutain, Annick, Bonnet-Brilhault, Frédérique, Hoorne, Yana, Joss, Shelagh, Chassevent, Anna K., Smith-Hicks, Constance, Loeys, Bart, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Mehta, Sarju G., Chung, Wendy K., Devriendt, Koenraad, Holder, Susan E., Jewett, Tamison, Baldwin, Lauren M., Wilson, William G., Towner, Shelley, Srivastava, Siddharth, Johnson, Hannah F., Daumer-Haas, Cornelia, Baethmann, Martina, Ruiz, Anna, Gabau, Elisabeth, Jain, Vani, Varghese, Vinod, Al-Beshri, Ali, Fulton, Stephen, Wechsberg, Oded, Orenstein, Naama, Prescott, Katrina, Childs, Anne-Marie, Faivre, Laurence, Moutton, Sébastien, Sullivan, Jennifer A., Shashi, Vandana, Koudijs, Suzanne M., Heijligers, Malou, Kivuva, Emma, McTague, Amy, Male, Alison, van Ierland, Yvette, Plecko, Barbara, Maystadt, Isabelle, Hamid, Rizwan, Hannig, Vickie L., Houge, Gunnar, and Janssens, Veerle

Published
2021
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14. SwissGenVar : A Platform for Clinical-Grade Interpretation of Genetic Variants to Foster Personalized Healthcare in Switzerland.

Author

Kraemer, Dennis, Terumalai, Dillenn, Famiglietti, Maria Livia, Filges, Isabel, Joset, Pascal, Koller, Samuel, Maurer, Fabienne, Meier, Stéphanie, Nouspikel, Thierry, Sanz, Javier, Zweier, Christiane, Abramowicz, Marc, Berger, Wolfgang, Cichon, Sven, Schaller, André, Superti-Furga, Andrea, Barbié, Valérie, and Rauch, Anita

Subjects
GENETIC variation, CLINICAL decision support systems, MEDICAL genetics, EXPERT evidence, NUCLEOTIDE sequencing
Abstract

Large-scale next-generation sequencing (NGS) germline testing is technically feasible today, but variant interpretation represents a major bottleneck in analysis workflows. This includes extensive variant prioritization, annotation, and time-consuming evidence curation. The scale of the interpretation problem is massive, and variants of uncertain significance (VUSs) are a challenge to personalized medicine. This challenge is further compounded by the complexity and heterogeneity of the standards used to describe genetic variants and the associated phenotypes when searching for relevant information to support clinical decision making. To address this, all five Swiss academic institutions for Medical Genetics joined forces with the Swiss Institute of Bioinformatics (SIB) to create SwissGenVar as a user-friendly nationwide repository and sharing platform for genetic variant data generated during routine diagnostic procedures and research sequencing projects. Its aim is to provide a protected environment for expert evidence sharing about individual variants to harmonize and upscale their significance interpretation at the clinical grade according to international standards. To corroborate the clinical assessment, the variant-related data will be combined with consented high-quality clinical information. Broader visibility will be achieved by interfacing with international databases, thus supporting global initiatives in personalized healthcare. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Genome-wide non-invasive prenatal testing in single- and multiple-pregnancies at any risk: Identification of maternal polymorphisms to reduce the number of unnecessary invasive confirmation testing

Author

Oneda, Beatrice, Sirleto, Pietro, Baldinger, Rosa, Taralczak, Malgorzata, Joset, Pascal, Zweier, Markus, Niedrist, Dunja, Azzarello-Burri, Silvia, Britschgi, Christian, Breymann, Christian, Ochsenbein-Kölble, Nicole, Burkhardt, Tilo, Wisser, Josef, Zimmermann, Roland, Steindl, Katharina, and Rauch, Anita

Published
2020
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16. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

Author

Pena, Loren, Shashi, Vandana, Schoch, Kelly, Sullivan, Jennifer A., Acosta, Maria T., Adams, David R., Aday, Aaron, Alejandro, Mercedes E., Allard, Patrick, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Barbouth, Deborah, Batzli, Gabriel F., Beggs, Alan H., Bellen, Hugo J., Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bick, David P., Birch, Camille L., Bivona, Stephanie, Bonnenmann, Carsten, Bonner, Devon, Boone, Braden E., Bostwick, Bret L., Briere, Lauren C., Brokamp, Elly, Brown, Donna M., Brush, Matthew, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Carrasquillo, Olveen, Peter Chang, Ta Chen, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., D'Souza, Precilla, Dasari, Surendra, Davids, Mariska, Davidson, Jean M., Dayal, Jyoti G., Dell'Angelica, Esteban C., Dhar, Shweta U., Dorrani, Naghmeh, Dorset, Daniel C., Douine, Emilie D., Draper, David D., Dries, Annika M., Duncan, Laura, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Enns, Gregory M., Esteves, Cecilia, Estwick, Tyra, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Friedman, Noah D., Gahl, William A., Godfrey, Rena A., Goldman, Alica M., Goldstein, David B., Gourdine, Jean-Philippe F., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A., High, Frances, Holm, Ingrid A., Hom, Jason, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jiang, Yong-hui, Johnston, Jean M., Jones, Angela L., Karaviti, Lefkothea, Kelley, Emily G., Koeller, David M., Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Korrick, Susan, Koziura, Mary, Krier, Joel B., Kyle, Jennifer E., Lalani, Seema R., Lam, Byron, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, Lazar, Jozef, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Levy, Shawn E., Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Markello, Thomas C., Marom, Ronit, Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, May, Thomas, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., Merker, Jason D., Metz, Thomas O., Might, Matthew, Morava-Kozicz, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nath, Avi, Nelson, Stan F., Newberry, J. Scott, Newman, John H., Nicholas, Sarah K., Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Postlethwait, John H., Potocki, Lorraine, Pusey, Barbara N., Renteri, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rowley, Robb K., Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Shakachite, Lisa, Sharma, Prashant, Shields, Kathleen, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Smith, Kevin S., Solnica-Krezel, Lilianna, Spillmann, Rebecca C., Stoler, Joan M., Stong, Nicholas, Sweetser, David A., Tamburro, Cecelia P., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Urv, Tiina K., Vogel, Tiphanie P., Waggott, Daryl M., Wahl, Colleen E., Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Waters, Katrina M., Webb-Robertson, Bobbie-Jo M., Wegner, Daniel, Westerfield, Monte, Wheeler, Matthew T., Wise, Anastasia L., Wolfe, Lynne A., Woods, Jeremy D., Worthey, Elizabeth A., Yamamoto, Shinya, Yang, John, Yoon, Amanda J., Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Gahl, William, Johnson, Brett V., Kumar, Raman, Oishi, Sabrina, Alexander, Suzy, Kasherman, Maria, Vega, Michelle Sanchez, Ivancevic, Atma, Gardner, Alison, Domingo, Deepti, Corbett, Mark, Parnell, Euan, Yoon, Sehyoun, Oh, Tracey, Lines, Matthew, Lefroy, Henrietta, Kini, Usha, Van Allen, Margot, Grønborg, Sabine, Mercier, Sandra, Küry, Sébastien, Bézieau, Stéphane, Pasquier, Laurent, Raynaud, Martine, Afenjar, Alexandra, Billette de Villemeur, Thierry, Keren, Boris, Désir, Julie, Van Maldergem, Lionel, Marangoni, Martina, Dikow, Nicola, Koolen, David A., VanHasselt, Peter M., Weiss, Marjan, Zwijnenburg, Petra, Sa, Joaquim, Reis, Claudia Falcao, López-Otín, Carlos, Santiago-Fernández, Olaya, Fernández-Jaén, Alberto, Rauch, Anita, Steindl, Katharina, Joset, Pascal, Goldstein, Amy, Madan-Khetarpal, Suneeta, Infante, Elena, Zackai, Elaine, Mcdougall, Carey, Narayanan, Vinodh, Ramsey, Keri, Mercimek-Andrews, Saadet, Pinto e Vairo, Filippo, Pichurin, Pavel N., Ewing, Sarah A., Barnett, Sarah S., Klee, Eric W., Perry, M. Scott, Koenig, Mary Kay, Keegan, Catherine E., Schuette, Jane L., Asher, Stephanie, Perilla-Young, Yezmin, Smith, Laurie D., Bhoj, Elizabeth, Kaplan, Paige, Li, Dong, Oegema, Renske, van Binsbergen, Ellen, van der Zwaag, Bert, Smeland, Marie Falkenberg, Cutcutache, Ioana, Page, Matthew, Armstrong, Martin, Lin, Angela E., Steeves, Marcie A., Hollander, Nicolette den, Hoffer, Mariëtte J.V., Reijnders, Margot R.F., Demirdas, Serwet, Koboldt, Daniel C., Bartholomew, Dennis, Mosher, Theresa Mihalic, Hickey, Scott E., Shieh, Christine, Sanchez-Lara, Pedro A., Graham, John M., Jr., Tezcan, Kamer, Schaefer, G.B., Danylchuk, Noelle R., Asamoah, Alexander, Jackson, Kelly E., Yachelevich, Naomi, Au, Margaret, Pérez-Jurado, Luis A., Kleefstra, Tjitske, Penzes, Peter, Wood, Stephen A., Burne, Thomas, Pierson, Tyler Mark, Piper, Michael, Gécz, Jozef, and Jolly, Lachlan A.

Published
2020
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17. Molecular and Phenotypic Characterization of the RORB-Related Disorder

Author

Gokce-Samar, Zeynep, primary, Vetro, Annalisa, additional, De Bellescize, Julitta, additional, Pisano, Tiziana, additional, Monteiro, Laloe, additional, Penaud, Noémie, additional, Korff, Christian M., additional, Fluss, Joel, additional, Marini, Carla, additional, Cesaroni, Elisabetta, additional, Alvarez, Blanca Mercedes, additional, Sanlaville, Damien, additional, Chatron, Nicolas, additional, Arzimanoglou, Alexis A., additional, Labalme, Audrey, additional, Cuddapah, Vishnu A., additional, Ruggiero, Sarah M., additional, Lecoquierre, Francois, additional, Nicolas, Gael, additional, Marie, Guerrot Anne, additional, Lebas, Axel, additional, Testard, Herve O., additional, Helbig, Katherine L., additional, Ruiz, Anna, additional, Ngoh, Adeline, additional, Kurian, Manju A., additional, Reid, Kimberley, additional, Spaull, Robert, additional, Joset, Pascal, additional, Ramantani, Georgia, additional, Steindl, Katharina, additional, Krenn, Martin, additional, Gerstl, Lucia, additional, Vieker, Silvia, additional, Craiu, Dana, additional, Pendziwiat, Manuela, additional, Haldeman-Englert, Chad, additional, Kanivets, Ilya, additional, Romanova, Irina, additional, Rajan, Deepa S., additional, Rosenfeld, Jill A., additional, Au, Margaret, additional, Grand, Katheryn, additional, Graham, John M., additional, Isapof, Arnaud, additional, Villeneuve, Nathalie, additional, Smol, Thomas, additional, Caumes, Roseline, additional, Zacher, Pia, additional, Neuser, Sonja, additional, Tinschert, Sigrid, additional, Platzer, Konrad, additional, Bartolomaeus, Tobias, additional, Mohnke, Ines, additional, Radtke, Maximilian, additional, Jamra, Rami Abou, additional, Helbig, Ingo, additional, Jansen, Floortje E., additional, Koop, Klaas, additional, Rudolf, Gabrielle, additional, Küry, Sebastien, additional, Courchet, Julien, additional, Guerrini, Renzo, additional, and Lesca, Gaetan, additional

Published
2023
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18. Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

Author

Picketts, David, primary, Mirzaa, Ghayda, additional, Yan, Keqin, additional, Relator, Raissa, additional, Timpano, Sara, additional, Yalcin, Binnaz, additional, Collins, Stephan, additional, Ziegler, Alban, additional, Pao, Emily, additional, Oyama, Nora, additional, Brischoux-Boucher, Elise, additional, PIARD, Juliette, additional, Monaghan, Kristin, additional, Sacoto, Maria Guillen, additional, Dobyns, William, additional, Park, Kristen, additional, Fernández-Mayoralas, Daniel, additional, Fernández-Jaén, Alberto, additional, Jayakar, Parul, additional, Brusco, Alfredo, additional, Antona, Vincenzo, additional, Giorgio, Elisa, additional, Kvarnung, Malin, additional, Isidor, Bertrand, additional, Conrad, Solène, additional, Cogné, Benjamin, additional, Deb, Wallid, additional, Stuurman, K.E., additional, Sterbova, Katalin, additional, Smal, Noor, additional, Weckhuysen, Sarah, additional, Oegema, Renske, additional, Innes, Micheil, additional, Latsko, Maeson, additional, Ben-Omran, Tawfeg, additional, Yeh, Rebecca, additional, Kruer, Michael, additional, Bakhtiari, Somayeh, additional, Papavasiliou, Antigone, additional, Moutton, Sébastien, additional, Nambot, Sophie, additional, Chanprasert, Sirisak, additional, Paolucci, Sarah, additional, Miller, Kait, additional, Burton, Barbara, additional, Kim, Katherine, additional, O'Heir, Emily, additional, Bruwer, Zandre, additional, Donald, Kirsten, additional, Kleefstra, Tjitske, additional, Goldstein, Amy, additional, Angle, Brad, additional, Bontempo, Kelly, additional, Miny, Peter, additional, Joset, Pascal, additional, Demurger, Florence, additional, Hobson, Emma, additional, Pang, Lewis, additional, Carpenter, Lori, additional, Li, Dong, additional, Bonneau, Dominique, additional, and Sadikovic, Bekim, additional

Published
2023
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19. Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures

Author

Zweier, Markus, Begemann, Anaïs, McWalter, Kirsty, Cho, Megan T., Abela, Lucia, Banka, Siddharth, Behring, Bettina, Berger, Andrea, Brown, Chester W., Carneiro, Maryline, Chen, Jiani, Cooper, Gregory M., Deciphering Developmental Disorders (DDD) Study, Finnila, Candice R., Guillen Sacoto, Maria J., Henderson, Alex, Hüffmeier, Ulrike, Joset, Pascal, Kerr, Bronwyn, Lesca, Gaetan, Leszinski, Gloria S., McDermott, John Henry, Meltzer, Meira R., Monaghan, Kristin G., Mostafavi, Roya, Õunap, Katrin, Plecko, Barbara, Powis, Zöe, Purcarin, Gabriela, Reimand, Tiia, Riedhammer, Korbinian M., Schreiber, John M., Sirsi, Deepa, Wierenga, Klaas J., Wojcik, Monica H., Papuc, Sorina M., Steindl, Katharina, Sticht, Heinrich, and Rauch, Anita

Published
2019
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20. The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study

Author

Papuc, Sorina M., Abela, Lucia, Steindl, Katharina, Begemann, Anaïs, Simmons, Thomas L., Schmitt, Bernhard, Zweier, Markus, Oneda, Beatrice, Socher, Eileen, Crowther, Lisa M., Wohlrab, Gabriele, Gogoll, Laura, Poms, Martin, Seiler, Michelle, Papik, Michael, Baldinger, Rosa, Baumer, Alessandra, Asadollahi, Reza, Kroell-Seger, Judith, Schmid, Regula, Iff, Tobias, Schmitt-Mechelke, Thomas, Otten, Karoline, Hackenberg, Annette, Addor, Marie-Claude, Klein, Andrea, Azzarello-Burri, Silvia, Sticht, Heinrich, Joset, Pascal, Plecko, Barbara, and Rauch, Anita

Published
2019
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21. Loss-of-function variants inCUL3cause a syndromic neurodevelopmental disorder

Author

Blackburn, Patrick R., primary, Ebstein, Frédéric, additional, Hsieh, Tzung-Chien, additional, Motta, Marialetizia, additional, Radio, Francesca Clementina, additional, Herkert, Johanna C., additional, Rinne, Tuula, additional, Thiffault, Isabelle, additional, Rapp, Michele, additional, Alders, Mariel, additional, Maas, Saskia, additional, Gerard, Bénédicte, additional, Smol, Thomas, additional, Vincent-Delorme, Catherine, additional, Cogné, Benjamin, additional, Isidor, Bertrand, additional, Vincent, Marie, additional, Bachmann-Gagescu, Ruxandra, additional, Rauch, Anita, additional, Joset, Pascal, additional, Ferrero, Giovanni Battista, additional, Ciolfi, Andrea, additional, Husson, Thomas, additional, Guerrot, Anne-Marie, additional, Bacino, Carlos, additional, Macmurdo, Colleen, additional, Thompson, Stephanie S., additional, Rosenfeld, Jill A., additional, Faivre, Laurence, additional, Mau-Them, Frederic Tran, additional, Deb, Wallid, additional, Vignard, Virginie, additional, Agrawal, Pankaj B., additional, Madden, Jill A., additional, Goldenberg, Alice, additional, Lecoquierre, François, additional, Zech, Michael, additional, Prokisch, Holger, additional, Necpál, Ján, additional, Jech, Robert, additional, Winkelmann, Juliane, additional, Koprušáková, Monika Turčanová, additional, Konstantopoulou, Vassiliki, additional, Younce, John R., additional, Shinawi, Marwan, additional, Mighton, Chloe, additional, Fung, Charlotte, additional, Morel, Chantal, additional, Ellis, Jordan Lerner-, additional, DiTroia, Stephanie, additional, Barth, Magalie, additional, Bonneau, Dominique, additional, Krapels, Ingrid, additional, Stegmann, Sander, additional, Schoot, Vyne van der, additional, Brunet, Theresa, additional, Bußmann, Cornelia, additional, Mignot, Cyril, additional, Courtin, Thomas, additional, Ravelli, Claudia, additional, Keren, Boris, additional, Ziegler, Alban, additional, Hasadsri, Linda, additional, Pichurin, Pavel N., additional, Klee, Eric W., additional, Grand, Katheryn, additional, Sanchez-Lara, Pedro A., additional, Krüger, Elke, additional, Bézieau, Stéphane, additional, Klinkhammer, Hannah, additional, Krawitz, Peter Michael, additional, Eichler, Evan E., additional, Tartaglia, Marco, additional, Küry, Sébastien, additional, and Wang, Tianyun, additional

Published
2023
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22. Cover

Author

Grether, Anna, primary, Ivanovski, Ivan, additional, Russo, Martina, additional, Begemann, Anaïs, additional, Steindl, Katharina, additional, Abela, Lucia, additional, Papik, Michael, additional, Zweier, Markus, additional, Oneda, Beatrice, additional, Joset, Pascal, additional, and Rauch, Anita, additional

Published
2023
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23. Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Author

Blackburn, Patrick R., Ebstein, Frédéric, Hsieh, Tzung-Chien, Motta, Marialetizia, Radio, Francesca Clementina, Herkert, Johanna C., Rinne, Tuula, Thiffault, Isabelle, Rapp, Michele, Alders, Mariel, Maas, Saskia, Gerard, Bénédicte, Smol, Thomas, Vincent-Delorme, Catherine, Cogné, Benjamin, Isidor, Bertrand, Vincent, Marie, Bachmann-Gagescu, Ruxandra, Rauch, Anita, Joset, Pascal, Ferrero, Giovanni Battista, Ciolfi, Andrea, Husson, Thomas, Guerrot, Anne-Marie, Bacino, Carlos, Macmurdo, Colleen, Thompson, Stephanie S., Rosenfeld, Jill A., Faivre, Laurence, Mau-Them, Frederic Tran, Deb, Wallid, Vignard, Virginie, Agrawal, Pankaj B., Madden, Jill A., Goldenberg, Alice, Lecoquierre, François, Zech, Michael, Prokisch, Holger, Necpál, Ján, Jech, Robert, Winkelmann, Juliane, Koprušáková, Monika Turčanová, Konstantopoulou, Vassiliki, Younce, John R., Shinawi, Marwan, Mighton, Chloe, Fung, Charlotte, Morel, Chantal, Ellis, Jordan Lerner, DiTroia, Stephanie, Barth, Magalie, Bonneau, Dominique, Krapels, Ingrid, Stegmann, Sander, van der Schoot, Vyne, Brunet, Theresa, Bußmann, Cornelia, Mignot, Cyril, Courtin, Thomas, Ravelli, Claudia, Keren, Boris, Ziegler, Alban, Hasadsri, Linda, Pichurin, Pavel N., Klee, Eric W., Grand, Katheryn, Sanchez-Lara, Pedro A., Krüger, Elke, Bézieau, Stéphane, Klinkhammer, Hannah, Krawitz, Peter Michael, Eichler, Evan E., Tartaglia, Marco, Küry, Sébastien, and Wang, Tianyun

Subjects
Article
Abstract

PURPOSE: De novo variants in CUL3 (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. METHODS: Genetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. RESULTS: We assembled a cohort of 35 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro . Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells. CONCLUSION: Our study further refines the clinical and mutational spectrum of CUL3 -associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.

Published
2023

24. The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies

Author

Grether, Anna, Ivanovski, Ivan, Russo, Martina, Begemann, Anaïs, Steindl, Katharina, Abela, Lucia, Papik, Michael, Zweier, Markus, Oneda, Beatrice, Joset, Pascal, Rauch, Anita, and University of Zurich

Subjects
whole genome sequencing, epileptic encephalopathy, 10036 Medical Clinic, 10039 Institute of Medical Genetics, diagnostic yield, Genetics, 570 Life sciences, biology, 610 Medicine & health, Molecular Biology, Genetics (clinical), whole exome sequencing
Published
2023

25. Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling

Author

Asadollahi, Reza, Strauss, Justin E, Zenker, Martin, Beuing, Oliver, Edvardson, Simon, Elpeleg, Orly, Strom, Tim M, Joset, Pascal, Niedrist, Dunja, Otte, Christine, Oneda, Beatrice, Boonsawat, Paranchai, Azzarello-Burri, Silvia, Bartholdi, Deborah, Papik, Michael, Zweier, Markus, Haas, Cordula, Ekici, Arif B, Baumer, Alessandra, Boltshauser, Eugen, Steindl, Katharina, Nothnagel, Michael, Schinzel, Albert, Stoeckli, Esther T, and Rauch, Anita

Published
2018
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26. Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons

Author

Asadollahi, Reza, primary, Delvendahl, Igor, additional, Muff, Rebecca, additional, Tan, Ge, additional, Rodríguez, Daymé González, additional, Turan, Soeren, additional, Russo, Martina, additional, Oneda, Beatrice, additional, Joset, Pascal, additional, Boonsawat, Paranchai, additional, Masood, Rahim, additional, Mocera, Martina, additional, Ivanovski, Ivan, additional, Baumer, Alessandra, additional, Bachmann-Gagescu, Ruxandra, additional, Schlapbach, Ralph, additional, Rehrauer, Hubert, additional, Steindl, Katharina, additional, Begemann, Anaïs, additional, Reis, André, additional, Winkler, Jürgen, additional, Winner, Beate, additional, Müller, Martin, additional, and Rauch, Anita, additional

Published
2023
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27. 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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29. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Author

Hiatt, Susan M., primary, Trajkova, Slavica, additional, Sebastiano, Matteo Rossi, additional, Partridge, E. Christopher, additional, Abidi, Fatima E., additional, Anderson, Ashlyn, additional, Ansar, Muhammad, additional, Antonarakis, Stylianos E., additional, Azadi, Azadeh, additional, Bachmann-Gagescu, Ruxandra, additional, Bartuli, Andrea, additional, Benech, Caroline, additional, Berkowitz, Jennifer L., additional, Betti, Michael J., additional, Brusco, Alfredo, additional, Cannon, Ashley, additional, Caron, Giulia, additional, Chen, Yanmin, additional, Cochran, Meagan E., additional, Coleman, Tanner F., additional, Crenshaw, Molly M., additional, Cuisset, Laurence, additional, Curry, Cynthia J., additional, Darvish, Hossein, additional, Demirdas, Serwet, additional, Descartes, Maria, additional, Douglas, Jessica, additional, Dyment, David A., additional, Elloumi, Houda Zghal, additional, Ermondi, Giuseppe, additional, Faoucher, Marie, additional, Farrow, Emily G., additional, Felker, Stephanie A., additional, Fisher, Heather, additional, Hurst, Anna C.E., additional, Joset, Pascal, additional, Kelly, Melissa A., additional, Kmoch, Stanislav, additional, Leadem, Benjamin R., additional, Lyons, Michael J., additional, Macchiaiolo, Marina, additional, Magner, Martin, additional, Mandrile, Giorgia, additional, Mattioli, Francesca, additional, McEown, Megan, additional, Meadows, Sarah K., additional, Medne, Livija, additional, Meeks, Naomi J.L., additional, Montgomery, Sarah, additional, Napier, Melanie P., additional, Natowicz, Marvin, additional, Newberry, Kimberly M., additional, Niceta, Marcello, additional, Noskova, Lenka, additional, Nowak, Catherine B., additional, Noyes, Amanda G., additional, Osmond, Matthew, additional, Prijoles, Eloise J., additional, Pugh, Jada, additional, Pullano, Verdiana, additional, Quélin, Chloé, additional, Rahimi-Aliabadi, Simin, additional, Rauch, Anita, additional, Redon, Sylvia, additional, Reymond, Alexandre, additional, Schwager, Caitlin R., additional, Sellars, Elizabeth A., additional, Scheuerle, Angela E., additional, Shukarova-Angelovska, Elena, additional, Skraban, Cara, additional, Stolerman, Elliot, additional, Sullivan, Bonnie R., additional, Tartaglia, Marco, additional, Thiffault, Isabelle, additional, Uguen, Kevin, additional, Umaña, Luis A., additional, van Bever, Yolande, additional, van der Crabben, Saskia N., additional, van Slegtenhorst, Marjon A., additional, Waisfisz, Quinten, additional, Washington, Camerun, additional, Rodan, Lance H., additional, Myers, Richard M., additional, and Cooper, Gregory M., additional

Published
2023
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31. 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

32. Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

Author

Genetica Klinische Genetica, Brain, Child Health, Picketts, David, Mirzaa, Ghayda, Yan, Keqin, Relator, Raissa, Timpano, Sara, Yalcin, Binnaz, Collins, Stephan, Ziegler, Alban, Pao, Emily, Oyama, Nora, Brischoux-Boucher, Elise, Piard, Juliette, Monaghan, Kristin, Sacoto, Maria Guillen, Dobyns, William, Park, Kristen, Fernández-Mayoralas, Daniel, Fernández-Jaén, Alberto, Jayakar, Parul, Brusco, Alfredo, Antona, Vincenzo, Giorgio, Elisa, Kvarnung, Malin, Isidor, Bertrand, Conrad, Solène, Cogné, Benjamin, Deb, Wallid, Stuurman, K E, Sterbova, Katalin, Smal, Noor, Weckhuysen, Sarah, Oegema, Renske, Innes, Micheil, Latsko, Maeson, Ben-Omran, Tawfeg, Yeh, Rebecca, Kruer, Michael, Bakhtiari, Somayeh, Papavasiliou, Antigone, Moutton, Sébastien, Nambot, Sophie, Chanprasert, Sirisak, Paolucci, Sarah, Miller, Kait, Burton, Barbara, Kim, Katherine, O'Heir, Emily, Bruwer, Zandre, Donald, Kirsten, Kleefstra, Tjitske, Goldstein, Amy, Angle, Brad, Bontempo, Kelly, Miny, Peter, Joset, Pascal, Demurger, Florence, Hobson, Emma, Pang, Lewis, Carpenter, Lori, Li, Dong, Bonneau, Dominique, Sadikovic, Bekim, Genetica Klinische Genetica, Brain, Child Health, Picketts, David, Mirzaa, Ghayda, Yan, Keqin, Relator, Raissa, Timpano, Sara, Yalcin, Binnaz, Collins, Stephan, Ziegler, Alban, Pao, Emily, Oyama, Nora, Brischoux-Boucher, Elise, Piard, Juliette, Monaghan, Kristin, Sacoto, Maria Guillen, Dobyns, William, Park, Kristen, Fernández-Mayoralas, Daniel, Fernández-Jaén, Alberto, Jayakar, Parul, Brusco, Alfredo, Antona, Vincenzo, Giorgio, Elisa, Kvarnung, Malin, Isidor, Bertrand, Conrad, Solène, Cogné, Benjamin, Deb, Wallid, Stuurman, K E, Sterbova, Katalin, Smal, Noor, Weckhuysen, Sarah, Oegema, Renske, Innes, Micheil, Latsko, Maeson, Ben-Omran, Tawfeg, Yeh, Rebecca, Kruer, Michael, Bakhtiari, Somayeh, Papavasiliou, Antigone, Moutton, Sébastien, Nambot, Sophie, Chanprasert, Sirisak, Paolucci, Sarah, Miller, Kait, Burton, Barbara, Kim, Katherine, O'Heir, Emily, Bruwer, Zandre, Donald, Kirsten, Kleefstra, Tjitske, Goldstein, Amy, Angle, Brad, Bontempo, Kelly, Miny, Peter, Joset, Pascal, Demurger, Florence, Hobson, Emma, Pang, Lewis, Carpenter, Lori, Li, Dong, Bonneau, Dominique, and Sadikovic, Bekim

Published
2023

33. Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Author

Blackburn, Patrick R; https://orcid.org/0000-0003-0658-1275, Ebstein, Frédéric, Hsieh, Tzung-Chien, Motta, Marialetizia; https://orcid.org/0000-0001-6592-910X, Radio, Francesca Clementina; https://orcid.org/0000-0003-1993-8018, Herkert, Johanna C; https://orcid.org/0000-0003-0461-9102, Rinne, Tuula, Thiffault, Isabelle, Rapp, Michele, Alders, Mariel, Maas, Saskia, Gérard, Bénédicte, Smol, Thomas; https://orcid.org/0000-0002-0119-5896, Vincent-Delorme, Catherine, Cogné, Benjamin; https://orcid.org/0000-0002-5503-6292, Isidor, Bertrand, Vincent, Marie, Bachmann-Gagescu, Ruxandra; https://orcid.org/0000-0002-3571-5271, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Ferrero, Giovanni Battista; https://orcid.org/0000-0002-3793-5788, Ciolfi, Andrea; https://orcid.org/0000-0002-6191-0978, Husson, Thomas; https://orcid.org/0000-0002-4088-5021, Guerrot, Anne-Marie, Bacino, Carlos; https://orcid.org/0000-0002-4342-5012, Macmurdo, Colleen, Thompson, Stephanie S, Rosenfeld, Jill A; https://orcid.org/0000-0001-5664-7987, Faivre, Laurence; https://orcid.org/0000-0001-9770-444X, Mau-Them, Frederic Tran; https://orcid.org/0000-0002-3795-9456, et al, Blackburn, Patrick R; https://orcid.org/0000-0003-0658-1275, Ebstein, Frédéric, Hsieh, Tzung-Chien, Motta, Marialetizia; https://orcid.org/0000-0001-6592-910X, Radio, Francesca Clementina; https://orcid.org/0000-0003-1993-8018, Herkert, Johanna C; https://orcid.org/0000-0003-0461-9102, Rinne, Tuula, Thiffault, Isabelle, Rapp, Michele, Alders, Mariel, Maas, Saskia, Gérard, Bénédicte, Smol, Thomas; https://orcid.org/0000-0002-0119-5896, Vincent-Delorme, Catherine, Cogné, Benjamin; https://orcid.org/0000-0002-5503-6292, Isidor, Bertrand, Vincent, Marie, Bachmann-Gagescu, Ruxandra; https://orcid.org/0000-0002-3571-5271, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Ferrero, Giovanni Battista; https://orcid.org/0000-0002-3793-5788, Ciolfi, Andrea; https://orcid.org/0000-0002-6191-0978, Husson, Thomas; https://orcid.org/0000-0002-4088-5021, Guerrot, Anne-Marie, Bacino, Carlos; https://orcid.org/0000-0002-4342-5012, Macmurdo, Colleen, Thompson, Stephanie S, Rosenfeld, Jill A; https://orcid.org/0000-0001-5664-7987, Faivre, Laurence; https://orcid.org/0000-0001-9770-444X, Mau-Them, Frederic Tran; https://orcid.org/0000-0002-3795-9456, and et al

Abstract

Purpose De novovariants inCUL3(Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants inCUL3,describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.ResultsWe assembled a cohort of 35 individuals with heterozygousCUL3variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants.CUL3LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugatesin vitro. Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells.ConclusionOur study further refines the clinical and mutational spectrum ofCUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.

Published
2023

34. The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort

Author

Zanoni, Paolo; https://orcid.org/0000-0001-9397-1989, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Sticht, Heinrich; https://orcid.org/0000-0001-5644-045X, Oneda, Beatrice; https://orcid.org/0000-0002-9732-0224, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Ivanovski, Ivan; https://orcid.org/0000-0002-0113-783X, Horn, Anselm H C; https://orcid.org/0000-0003-3539-8103, Cabello, Elena María; https://orcid.org/0000-0003-3006-3558, Laube, Julia, Zweier, Markus; https://orcid.org/0000-0001-8290-0413, Baumer Wolz, Alessandra; https://orcid.org/0000-0001-5124-4740, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Khan, Nadia; https://orcid.org/0000-0001-5077-6622, Zanoni, Paolo; https://orcid.org/0000-0001-9397-1989, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Sticht, Heinrich; https://orcid.org/0000-0001-5644-045X, Oneda, Beatrice; https://orcid.org/0000-0002-9732-0224, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Ivanovski, Ivan; https://orcid.org/0000-0002-0113-783X, Horn, Anselm H C; https://orcid.org/0000-0003-3539-8103, Cabello, Elena María; https://orcid.org/0000-0003-3006-3558, Laube, Julia, Zweier, Markus; https://orcid.org/0000-0001-8290-0413, Baumer Wolz, Alessandra; https://orcid.org/0000-0001-5124-4740, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, and Khan, Nadia; https://orcid.org/0000-0001-5077-6622

Abstract

Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings. The two largest subgroups in our cohort consisted of RNF213 and neurofibromatosis type 1 (NF1) patients. While deleterious RNF213 variants were associated with a severe MMA clinical course with early symptom onset, frequent posterior cerebral artery involvement and higher stroke rates in multiple territories, NF1 patients had a similar infarct burden compared to non-NF1 individuals and were often diagnosed incidentally during routine MRIs. Additionally, we found that MMA-associated RNF213 variants have lower predicted functional impact compared to those associated with aortic disease. We also raise the question of MMA as a feature of recurrent as well as rare chromosomal imbalances and further support the possible association of MMA with STAT3 deficiency. In conclusion, we provide a comprehensive characterization at the genetic and clinical level of a large exclusively pediatric MMA population. Due to the clinical differences found across genetic subgroups, we propose genetic testing for risk stratification as part of the routine assessment of pediatric MMA patients.

Published
2023

35. Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons

Author

Asadollahi, Reza; https://orcid.org/0000-0002-1497-0564, Delvendahl, Igor; https://orcid.org/0000-0002-6151-2363, Muff, Rebecca; https://orcid.org/0000-0001-9779-2603, Tan, Ge; https://orcid.org/0000-0003-0026-8739, Rodríguez, Daymé González, Turan, Soeren, Russo, Martina, Oneda, Beatrice; https://orcid.org/0000-0002-9732-0224, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Boonsawat, Paranchai; https://orcid.org/0000-0003-3059-1916, Masood, Rahim, Mocera, Martina; https://orcid.org/0009-0004-0613-9238, Ivanovski, Ivan; https://orcid.org/0000-0002-0113-783X, Baumer Wolz, Alessandra; https://orcid.org/0000-0001-5124-4740, Bachmann-Gagescu, Ruxandra; https://orcid.org/0000-0002-3571-5271, Schlapbach, Ralph; https://orcid.org/0000-0002-7488-4262, Rehrauer, Hubert; https://orcid.org/0000-0001-7612-9394, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Begemann, Anaïs; https://orcid.org/0000-0001-6762-0819, Reis, André; https://orcid.org/0000-0002-6301-6363, Winkler, Jürgen, Winner, Beate, Müller, Martin; https://orcid.org/0000-0003-1624-6761, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Asadollahi, Reza; https://orcid.org/0000-0002-1497-0564, Delvendahl, Igor; https://orcid.org/0000-0002-6151-2363, Muff, Rebecca; https://orcid.org/0000-0001-9779-2603, Tan, Ge; https://orcid.org/0000-0003-0026-8739, Rodríguez, Daymé González, Turan, Soeren, Russo, Martina, Oneda, Beatrice; https://orcid.org/0000-0002-9732-0224, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Boonsawat, Paranchai; https://orcid.org/0000-0003-3059-1916, Masood, Rahim, Mocera, Martina; https://orcid.org/0009-0004-0613-9238, Ivanovski, Ivan; https://orcid.org/0000-0002-0113-783X, Baumer Wolz, Alessandra; https://orcid.org/0000-0001-5124-4740, Bachmann-Gagescu, Ruxandra; https://orcid.org/0000-0002-3571-5271, Schlapbach, Ralph; https://orcid.org/0000-0002-7488-4262, Rehrauer, Hubert; https://orcid.org/0000-0001-7612-9394, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Begemann, Anaïs; https://orcid.org/0000-0001-6762-0819, Reis, André; https://orcid.org/0000-0002-6301-6363, Winkler, Jürgen, Winner, Beate, Müller, Martin; https://orcid.org/0000-0003-1624-6761, and Rauch, Anita; https://orcid.org/0000-0003-2930-3163

Abstract

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)], and compared them to neurons from an epileptic encephalopathy patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. By contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency, and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further i

Published
2023

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

Author

Sheppard, Sarah E; https://orcid.org/0000-0003-3480-8123, Bryant, Laura; https://orcid.org/0000-0001-8483-8940, Wickramasekara, Rochelle N; https://orcid.org/0000-0003-3090-9357, Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi; https://orcid.org/0000-0002-3892-8213, Hulen, Jason, Watson, Cynthia J, Faundes, Victor; https://orcid.org/0000-0002-6746-0103, Duffourd, Yannis, Lee, Pearl; https://orcid.org/0000-0002-1274-2891, Simon, M Celeste; https://orcid.org/0000-0001-9106-447X, de la Cruz, Xavier; https://orcid.org/0000-0002-9738-8472, Padilla, Natália; https://orcid.org/0000-0002-7872-2279, Flores-Mendez, Marco; https://orcid.org/0000-0002-0524-9740, Akizu, Naiara; https://orcid.org/0000-0001-9222-6960, Smiler, Jacqueline; https://orcid.org/0000-0002-3201-228X, Da Silva, Renata Pellegrino, Li, Dong; https://orcid.org/0000-0002-2265-6727, March, Michael; https://orcid.org/0000-0001-9173-6862, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto; https://orcid.org/0000-0002-3843-4520, Choa, Zhao Xiang; https://orcid.org/0000-0002-1838-7931, Lim, Chin Yan; https://orcid.org/0000-0002-1585-002X, Dubourg, Christèle; https://orcid.org/0000-0003-1345-4522, Journel, Hubert, Demurger, Florence, Mulhern, Maureen; https://orcid.org/0000-0001-8642-4741, Akman, Cigdem, Lippa, Natalie; https://orcid.org/0000-0002-7316-1476, 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, et al, Sheppard, Sarah E; https://orcid.org/0000-0003-3480-8123, Bryant, Laura; https://orcid.org/0000-0001-8483-8940, Wickramasekara, Rochelle N; https://orcid.org/0000-0003-3090-9357, Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi; https://orcid.org/0000-0002-3892-8213, Hulen, Jason, Watson, Cynthia J, Faundes, Victor; https://orcid.org/0000-0002-6746-0103, Duffourd, Yannis, Lee, Pearl; https://orcid.org/0000-0002-1274-2891, Simon, M Celeste; https://orcid.org/0000-0001-9106-447X, de la Cruz, Xavier; https://orcid.org/0000-0002-9738-8472, Padilla, Natália; https://orcid.org/0000-0002-7872-2279, Flores-Mendez, Marco; https://orcid.org/0000-0002-0524-9740, Akizu, Naiara; https://orcid.org/0000-0001-9222-6960, Smiler, Jacqueline; https://orcid.org/0000-0002-3201-228X, Da Silva, Renata Pellegrino, Li, Dong; https://orcid.org/0000-0002-2265-6727, March, Michael; https://orcid.org/0000-0001-9173-6862, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto; https://orcid.org/0000-0002-3843-4520, Choa, Zhao Xiang; https://orcid.org/0000-0002-1838-7931, Lim, Chin Yan; https://orcid.org/0000-0002-1585-002X, Dubourg, Christèle; https://orcid.org/0000-0003-1345-4522, Journel, Hubert, Demurger, Florence, Mulhern, Maureen; https://orcid.org/0000-0001-8642-4741, Akman, Cigdem, Lippa, Natalie; https://orcid.org/0000-0002-7316-1476, 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, and et al

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 KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Published
2023

37. SwissGenVar: A platform for clinical grade interpretation of genetic variants to foster personalized health care in Switzerland

Author

Kraemer, Dennis; https://orcid.org/0000-0001-7084-2068, Terumalai, Dillenn, Famiglietti, Maria Livia; https://orcid.org/0000-0002-5283-6593, Filges, Isabel; https://orcid.org/0000-0002-2149-6354, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Koller, Samuel; https://orcid.org/0000-0003-0965-0539, Maurer, Fabienne; https://orcid.org/0000-0002-6837-5963, Meier, Stéphanie, Nouspikel, Thierry; https://orcid.org/0000-0002-6650-9147, Sanz, Javier; https://orcid.org/0000-0001-6386-0313, Zweier, Christiane; https://orcid.org/0000-0001-8002-2020, Abramowicz, Marc; https://orcid.org/0000-0003-0623-8768, Berger, Wolfgang; https://orcid.org/0000-0002-0370-3815, Cichon, Sven; https://orcid.org/0000-0002-9475-086X, Schaller, André; https://orcid.org/0000-0001-5174-5764, Superti-Furga, Andrea; https://orcid.org/0000-0002-3543-7531, Barbié, Valérie; https://orcid.org/0009-0006-8085-9393, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Kraemer, Dennis; https://orcid.org/0000-0001-7084-2068, Terumalai, Dillenn, Famiglietti, Maria Livia; https://orcid.org/0000-0002-5283-6593, Filges, Isabel; https://orcid.org/0000-0002-2149-6354, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Koller, Samuel; https://orcid.org/0000-0003-0965-0539, Maurer, Fabienne; https://orcid.org/0000-0002-6837-5963, Meier, Stéphanie, Nouspikel, Thierry; https://orcid.org/0000-0002-6650-9147, Sanz, Javier; https://orcid.org/0000-0001-6386-0313, Zweier, Christiane; https://orcid.org/0000-0001-8002-2020, Abramowicz, Marc; https://orcid.org/0000-0003-0623-8768, Berger, Wolfgang; https://orcid.org/0000-0002-0370-3815, Cichon, Sven; https://orcid.org/0000-0002-9475-086X, Schaller, André; https://orcid.org/0000-0001-5174-5764, Superti-Furga, Andrea; https://orcid.org/0000-0002-3543-7531, Barbié, Valérie; https://orcid.org/0009-0006-8085-9393, and Rauch, Anita; https://orcid.org/0000-0003-2930-3163

Abstract

Large-scale next-generation sequencing (NGS) germline testing is technically feasible today, but variant interpretation represents a major bottleneck in analysis workflows including the extensive variant prioritization, annotation, and time-consuming evidence curation. The scale of the interpretation problem is massive, and variants of uncertain significance (VUS) are a challenge to personalized medicine. This challenge is further compounded by the complexity and heterogeneity of standards used to describe genetic variants and associated phenotypes when searching for relevant information to inform clinical decision-making. For this purpose, all five Swiss academic Medical Genetics Institutions joined forces with the Swiss Institute of Bioinformatics (SIB) to create SwissGenVar as a user-friendly nationwide repository and sharing platform for genetic variant data generated during routine diagnostic procedures and research sequencing projects. Its objective is to provide a protected environment for expert evidence sharing about individual variants to harmonize and up-scale their significance interpretation at clinical grade following international standards. To corroborate the clinical assessment, the variant-related data are combined with consented high-quality clinical information. Broader visibility will be gained by interfacing with international databases, thus supporting global initiatives in personalized health care.

Published
2023

38. 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, Simon, M Celeste, 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, Joset, Pascal, Steindl, Katharina, Rauch, Anita, et al, and University of Zurich

Subjects
1000 Multidisciplinary, Methyltransferases / genetics, 10039 Institute of Medical Genetics, Knockout, 610 Medicine & health, Haploinsufficiency, Methyltransferases, Mice, Phenotype, Megalencephaly, 10036 Medical Clinic, Neurodevelopmental Disorders* / genetics, 570 Life sciences, biology, Animals, Humans
Published
2023

39. SwissGenVar: A platform for clinical grade interpretation of genetic variants to foster personalized health care in Switzerland

Author

Kraemer, Dennis, primary, Terumalai, Dillenn, additional, Famiglietti, Maria Livia, additional, Filges, Isabel, additional, Joset, Pascal, additional, Koller, Samuel, additional, Maurer, Fabienne, additional, Meier, Stéphanie, additional, Nouspikel, Thierry, additional, Sanz, Javier, additional, Zweier, Christiane, additional, Abramowicz, Marc, additional, Berger, Wolfgang, additional, Cichon, Sven, additional, Schaller, André, additional, Superti-Furga, Andrea, additional, Barbié, Valérie, additional, and Rauch, Anita, additional

Published
2023
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40. A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

Author

Snijders Blok, Lot, primary, Verseput, Jolijn, additional, Rots, Dmitrijs, additional, Venselaar, Hanka, additional, Innes, A. Micheil, additional, Stumpel, Connie, additional, Õunap, Katrin, additional, Reinson, Karit, additional, Seaby, Eleanor G., additional, McKee, Shane, additional, Burton, Barbara, additional, Kim, Katherine, additional, van Hagen, Johanna M., additional, Waisfisz, Quinten, additional, Joset, Pascal, additional, Steindl, Katharina, additional, Rauch, Anita, additional, Li, Dong, additional, Zackai, Elaine H., additional, Sheppard, Sarah E., additional, Keena, Beth, additional, Hakonarson, Hakon, additional, Roos, Andreas, additional, Kohlschmidt, Nicolai, additional, Cereda, Anna, additional, Iascone, Maria, additional, Rebessi, Erika, additional, Kernohan, Kristin D., additional, Campeau, Philippe M., additional, Millan, Francisca, additional, Taylor, Jesse A., additional, Lochmüller, Hanns, additional, Higgs, Martin R., additional, Goula, Amalia, additional, Bernhard, Birgitta, additional, Velasco, Danita J., additional, Schmanski, Andrew A., additional, Stark, Zornitza, additional, Gallacher, Lyndon, additional, Pais, Lynn, additional, Marcogliese, Paul C., additional, Yamamoto, Shinya, additional, Raun, Nicholas, additional, Jakub, Taryn E., additional, Kramer, Jamie M., additional, den Hoed, Joery, additional, Fisher, Simon E., additional, Brunner, Han G., additional, and Kleefstra, Tjitske, additional

Published
2023
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42. SwissGenVar: A platform for clinical grade interpretation of genetic variants to foster personalized health care in Switzerland

Author

Kraemer, Dennis, Terumalai, Dillenn, Famiglietti, Maria Livia, Filges, Isabel, Joset, Pascal, Koller, Samuel, Maurer, Fabienne, Meier, Stéphanie, Nouspikel, Thierry, Sanz, Javier, Zweier, Christiane, Abramowicz, Marc, Berger, Wolfgang, Cichon, Sven, Schaller, André, Superti-Furga, Andrea, Barbié, Valérie, Rauch, Anita, and University of Zurich

Subjects
11124 Institute of Medical Molecular Genetics, expert, 10039 Institute of Medical Genetics, NGS, genotype, 570 Life sciences, biology, 610 Medicine & health, personalized medicine, SwissGenVar, Switzerland, curated variant interpretation, national mutation database, phenotype database
Published
2023

43. Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Author

Blackburn, Patrick R, Ebstein, Frédéric, Hsieh, Tzung-Chien, Motta, Marialetizia, Radio, Francesca Clementina, Herkert, Johanna C, Rinne, Tuula, Thiffault, Isabelle, Rapp, Michele, Alders, Mariel, Maas, Saskia, Gérard, Bénédicte, Smol, Thomas, Vincent-Delorme, Catherine, Cogné, Benjamin, Isidor, Bertrand, Vincent, Marie, Bachmann-Gagescu, Ruxandra, Rauch, Anita, Joset, Pascal, Ferrero, Giovanni Battista, Ciolfi, Andrea, Husson, Thomas, Guerrot, Anne-Marie, Bacino, Carlos, Macmurdo, Colleen, Thompson, Stephanie S, Rosenfeld, Jill A, Faivre, Laurence, Mau-Them, Frederic Tran, et al, and University of Zurich

Subjects
Genomic Medicine, 10039 Institute of Medical Genetics, 570 Life sciences, biology, 610 Medicine & health, 10124 Institute of Molecular Life Sciences, Genetic Medicine
Published
2023
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44. Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons

Author

Asadollahi, Reza, Delvendahl, Igor, Muff, Rebecca, Tan, Ge, Rodríguez, Daymé González, Turan, Soeren, Russo, Martina, Oneda, Beatrice, Joset, Pascal, Boonsawat, Paranchai, Masood, Rahim, Mocera, Martina, Ivanovski, Ivan, Baumer Wolz, Alessandra, Bachmann-Gagescu, Ruxandra, Schlapbach, Ralph, Rehrauer, Hubert, Steindl, Katharina, Begemann, Anaïs, Reis, André, Winkler, Jürgen, Winner, Beate, Müller, Martin, Rauch, Anita, and University of Zurich

Subjects
10036 Medical Clinic, 10039 Institute of Medical Genetics, 10076 Center for Integrative Human Physiology, Genetics, 570 Life sciences, biology, 610 Medicine & health, 10071 Functional Genomics Center Zurich, General Medicine, 10064 Neuroscience Center Zurich, Molecular Biology, 10124 Institute of Molecular Life Sciences, Genetics (clinical)
Published
2023
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45. Challenges for the implementation of next generation sequencing-based expanded carrier screening: Lessons learned from the ciliopathies

Author

Vintschger, Ella, Kraemer, Dennis, Joset, Pascal, Horn, Anselm H C, Rauch, Anita, Sticht, Heinrich, Bachmann-Gagescu, Ruxandra, University of Zurich, and Bachmann-Gagescu, Ruxandra

Subjects
next generation sequencing, 2716 Genetics (clinical), pregnancy outcome, medical genetics, 10039 Institute of Medical Genetics, expanded carrier screening, 610 Medicine & health, 10124 Institute of Molecular Life Sciences, 1311 Genetics, NGS, Genetics, 570 Life sciences, biology, risk factors, CS, genetic counceling, Genetics (clinical)
Abstract

Next generation sequencing (NGS) can detect carrier status for rare recessive disorders, informing couples about their reproductive risk. The recent ACMG recommendations support offering NGS-based carrier screening (NGS-CS) in an ethnic and population-neutral manner for all genes that have a carrier frequency >1/200 (based on GnomAD). To evaluate current challenges for NGS-CS, we focused on the ciliopathies, a well-studied group of rare recessive disorders. We analyzed 118 ciliopathy genes by whole exome sequencing in ~400 healthy local individuals and ~1000 individuals from the UK1958-birth cohort. We found 20% of healthy individuals (1% of couples) to be carriers of reportable variants in a ciliopathy gene, while 50% (4% of couples) carry variants of uncertain significance (VUS). This large proportion of VUS is partly explained by the limited utility of the ACMG/AMP variant-interpretation criteria in healthy individuals, where phenotypic match or segregation criteria cannot be used. Most missense variants are thus classified as VUS and not reported, which reduces the negative predictive value of the screening test. We show how gene-specific variation patterns and structural protein information can help prioritize variants most likely to be disease-causing, for (future) functional assays. Even when considering only strictly pathogenic variants, the observed carrier frequency is substantially higher than expected based on estimated disease prevalence, challenging the 1/200 carrier frequency cut-off proposed for choice of genes to screen. Given the challenges linked to variant interpretation in healthy individuals and the uncertainties about true carrier frequencies, genetic counseling must clearly disclose these limitations of NGS-CS.

Published
2022

46. Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

Author

Hiatt, Susan M., primary, Trajkova, Slavica, additional, Sebastiano, Matteo Rossi, additional, Partridge, E. Christopher, additional, Abidi, Fatima E., additional, Anderson, Ashlyn, additional, Ansar, Muhammad, additional, Antonarakis, Stylianos E., additional, Azadi, Azadeh, additional, Bachmann-Gagescu, Ruxandra, additional, Bartuli, Andrea, additional, Benech, Caroline, additional, Berkowitz, Jennifer L., additional, Betti, Michael J., additional, Brusco, Alfredo, additional, Cannon, Ashley, additional, Caron, Giulia, additional, Chen, Yanmin, additional, Crenshaw, Molly M., additional, Cuisset, Laurence, additional, Curry, Cynthia J., additional, Darvish, Hossein, additional, Demirdas, Serwet, additional, Descartes, Maria, additional, Douglas, Jessica, additional, Dyment, David A., additional, Elloumi, Houda Zghal, additional, Ermondi, Giuseppe, additional, Faoucher, Marie, additional, Farrow, Emily G., additional, Felker, Stephanie A., additional, Fisher, Heather, additional, Hurst, Anna C. E., additional, Joset, Pascal, additional, Kmoch, Stanislav, additional, Leadem, Benjamin R., additional, Macchiaiolo, Marina, additional, Magner, Martin, additional, Mandrile, Giorgia, additional, Mattioli, Francesca, additional, McEown, Megan, additional, Meadows, Sarah K., additional, Medne, Livija, additional, Meeks, Naomi J. L., additional, Montgomery, Sarah, additional, Napier, Melanie P., additional, Natowicz, Marvin, additional, Newberry, Kimberly M., additional, Niceta, Marcello, additional, Noskova, Lenka, additional, Nowak, Catherine, additional, Noyes, Amanda G., additional, Osmond, Matthew, additional, Pullano, Verdiana, additional, Quélin, Chloé, additional, Rahimi-Aliabadi, Simin, additional, Rauch, Anita, additional, Redon, Sylvia, additional, Reymond, Alexandre, additional, Schwager, Caitlin R., additional, Sellars, Elizabeth A., additional, Scheuerle, Angela, additional, Shukarova-Angelovska, Elena, additional, Skraban, Cara, additional, Sullivan, Bonnie R., additional, Tartaglia, Marco, additional, Thiffault, Isabelle, additional, Uguen, Kevin, additional, Umaña, Luis A., additional, van Bever, Yolande, additional, van der Crabben, Saskia N., additional, van Slegtenhorst, Marjon A., additional, Waisfisz, Quinten, additional, Myers, Richard M., additional, and Cooper, Gregory M., additional

Published
2022
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47. 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

50. Assessing clinical utility of preconception expanded carrier screening regarding residual risk for neurodevelopmental disorders

Author

Boonsawat, Paranchai; https://orcid.org/0000-0003-3059-1916, Horn, Anselm H C; https://orcid.org/0000-0003-3539-8103, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Baumer Wolz, Alessandra; https://orcid.org/0000-0001-5124-4740, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Kraemer, Dennis; https://orcid.org/0000-0001-7084-2068, Bahr, Angela; https://orcid.org/0000-0001-9759-2599, Ivanovski, Ivan; https://orcid.org/0000-0002-0113-783X, Cabello Ferrete, Elena; https://orcid.org/0000-0003-3006-3558, Papik, Michael; https://orcid.org/0009-0009-0775-2700, Zweier, Markus; https://orcid.org/0000-0001-8290-0413, Oneda, Beatrice; https://orcid.org/0000-0002-9732-0224, Sirleto, Pietro; https://orcid.org/0000-0001-5292-3315, Burkhardt, Tilo; https://orcid.org/0000-0001-7043-9973, Sticht, Heinrich; https://orcid.org/0000-0001-5644-045X, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, Boonsawat, Paranchai; https://orcid.org/0000-0003-3059-1916, Horn, Anselm H C; https://orcid.org/0000-0003-3539-8103, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Baumer Wolz, Alessandra; https://orcid.org/0000-0001-5124-4740, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Kraemer, Dennis; https://orcid.org/0000-0001-7084-2068, Bahr, Angela; https://orcid.org/0000-0001-9759-2599, Ivanovski, Ivan; https://orcid.org/0000-0002-0113-783X, Cabello Ferrete, Elena; https://orcid.org/0000-0003-3006-3558, Papik, Michael; https://orcid.org/0009-0009-0775-2700, Zweier, Markus; https://orcid.org/0000-0001-8290-0413, Oneda, Beatrice; https://orcid.org/0000-0002-9732-0224, Sirleto, Pietro; https://orcid.org/0000-0001-5292-3315, Burkhardt, Tilo; https://orcid.org/0000-0001-7043-9973, Sticht, Heinrich; https://orcid.org/0000-0001-5644-045X, and Rauch, Anita; https://orcid.org/0000-0003-2930-3163

Abstract

The magnitude of clinical utility of preconception expanded carrier screening (ECS) concerning its potential to reduce the risk of affected offspring is unknown. Since neurodevelopmental disorders (NDDs) in their offspring is a major concern of parents-to-be, we addressed the question of residual risk by assessing the risk-reduction potential for NDDs in a retrospective study investigating ECS with different criteria for gene selection and definition of pathogenicity. We used exome sequencing data from 700 parents of children with NDDs and blindly screened for carrier-alleles in up to 3046 recessive/X-linked genes. Depending on variant pathogenicity thresholds and gene content, NDD-risk-reduction potential was up to 43.5% in consanguineous, and 5.1% in nonconsanguineous couples. The risk-reduction-potential was compromised by underestimation of pathogenicity of missense variants (false-negative-rate 4.6%), inherited copy-number variants and compound heterozygosity of one inherited and one de novo variant (0.9% each). Adherence to the ACMG recommendations of restricting ECS to high-frequency genes in nonconsanguineous couples would more than halve the detectable inherited NDD-risk. Thus, for optimized clinical utility of ECS, screening in recessive/X-linked genes regardless of their frequency (ACMG Tier-4) and sensible pathogenicity thresholds should be considered for all couples seeking ECS.

Published
2022

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