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2. Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders

Author

Langhammer, Franziska, Maroofian, Reza, Badar, Rueda, Gregor, Anne, Rochman, Michelle, Ratliff, Jeffrey B., Koopmans, Marije, Herget, Theresia, Hempel, Maja, Kortüm, Fanny, Heron, Delphine, Mignot, Cyril, Keren, Boris, Brooks, Susan, Botti, Christina, Ben-Zeev, Bruria, Argilli, Emanuela, Sherr, Elliot H., Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Bakhtiari, Somayeh, Kruer, Michael C., Salih, Mustafa A., Kuechler, Alma, Muller, Eric A., Blocker, Karli, Kuismin, Outi, Park, Kristen L., Kochhar, Aaina, Brown, Kathleen, Ramanathan, Subhadra, Clark, Robin D., Elgizouli, Magdeldin, Melikishvili, Gia, Tabatadze, Nazhi, Stark, Zornitza, Mirzaa, Ghayda M., Ong, Jinfon, Grasshoff, Ute, Bevot, Andrea, von Wintzingerode, Lydia, Jamra, Rami A., Hennig, Yvonne, Goldenberg, Paula, Al Alam, Chadi, Charif, Majida, Boulouiz, Redouane, Bellaoui, Mohammed, Amrani, Rim, Al Mutairi, Fuad, Tamim, Abdullah M., Abdulwahab, Firdous, Alkuraya, Fowzan S., Khouj, Ebtissal M., Alvi, Javeria R., Sultan, Tipu, Hashemi, Narges, Karimiani, Ehsan G., Ashrafzadeh, Farah, Imannezhad, Shima, Efthymiou, Stephanie, Houlden, Henry, Sticht, Heinrich, and Zweier, Christiane

Published
2023
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3. Clustered variants in the 5′ coding region of TRA2B cause a distinctive neurodevelopmental syndrome

Author

Ramond, Francis, Dalgliesh, Caroline, Grimmel, Mona, Wechsberg, Oded, Vetro, Annalisa, Guerrini, Renzo, FitzPatrick, David, Poole, Rebecca L., Lebrun, Marine, Bayat, Allan, Grasshoff, Ute, Bertrand, Miriam, Witt, Dennis, Turnpenny, Peter D., Faundes, Víctor, Santa María, Lorena, Mendoza Fuentes, Carolina, Mabe, Paulina, Hussain, Shaun A., Mullegama, Sureni V., Torti, Erin, Oehl-Jaschkowitz, Barbara, Salmon, Lina Basel, Orenstein, Naama, Shahar, Noa Ruhrman, Hagari, Ofir, Bazak, Lily, Hoffjan, Sabine, Prada, Carlos E., Haack, Tobias, and Elliott, David J.

Published
2023
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4. Confirmation and expansion of the phenotype of the TCEAL1-related neurodevelopmental disorder

Author

Albuainain, Fatimah, Shi, Yuwei, Lor-Zade, Sarah, Hüffmeier, Ulrike, Pauly, Melissa, Reis, André, Faivre, Laurence, Maraval, Julien, Bruel, Ange Line, Them, Frédéric Tran Mau, Haack, Tobias B., Grasshoff, Ute, Horber, Veronka, Schot, Rachel, van Slegtenhorst, Marjon, Wilke, Martina, Barakat, Tahsin Stefan, Albuainain, Fatimah, Shi, Yuwei, Lor-Zade, Sarah, Hüffmeier, Ulrike, Pauly, Melissa, Reis, André, Faivre, Laurence, Maraval, Julien, Bruel, Ange Line, Them, Frédéric Tran Mau, Haack, Tobias B., Grasshoff, Ute, Horber, Veronka, Schot, Rachel, van Slegtenhorst, Marjon, Wilke, Martina, and Barakat, Tahsin Stefan

Abstract

Numerous contiguous gene deletion syndromes causing neurodevelopmental disorders have previously been defined using cytogenetics for which only in the current genomic era the disease-causing genes have become elucidated. One such example is deletion at Xq22.2, previously associated with a neurodevelopmental disorder which has more recently been found to be caused by de novo loss-of-function variants in TCEAL1. So far, a single study reported six unrelated individuals with this monogenetic disorder, presenting with syndromic features including developmental delay especially affecting expressive speech, intellectual disability, autistic-like behaviors, hypotonia, gait abnormalities and mild facial dysmorphism, in addition to ocular, gastrointestinal, and immunologic abnormalities. Here we report on four previously undescribed individuals, including two adults, with de novo truncating variants in TCEAL1, identified through trio exome or genome sequencing, further delineating the phenotype of the TCEAL1-related disorder. Whereas overall we identify similar features compared to the original report, we also highlight features in our adult individuals including hyperphagia, obesity, and endocrine abnormalities including hyperinsulinemia, hyperandrogenemia, and polycystic ovarian syndrome. X chromosome inactivation and RNA-seq studies further provide functional insights in the molecular mechanisms. Together this report expands the phenotypic and molecular spectrum of the TCEAL1-related disorder which will be useful for counseling of newly identified individuals and their families.

Published
2024

5. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Author

van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Wödl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F.J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W.Y., Chung, Brain H.Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hülya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, López-González, Vanesa, Maas, Saskia, Mancini, Grazia M.S., Marcelis, Carlo, Martinez, Francisco, Maystadt, Isabelle, McGuire, Marianne, McKee, Shane, Mehta, Sarju, Metcalfe, Kay, Milunsky, Jeff, Mizuno, Seiji, Moeschler, John B., Netzer, Christian, Ockeloen, Charlotte W., Oehl-Jaschkowitz, Barbara, Okamoto, Nobuhiko, Olminkhof, Sharon N.M., Orellana, Carmen, Pasquier, Laurent, Pottinger, Caroline, Riehmer, Vera, Robertson, Stephen P., Roifman, Maian, Rooryck, Caroline, Ropers, Fabienne G., Rosello, Monica, Ruivenkamp, Claudia A.L., Sagiroglu, Mahmut S., Sallevelt, Suzanne C.E.H., Sanchis Calvo, Amparo, Simsek-Kiper, Pelin O., Soares, Gabriela, Solaeche, Lucia, Sonmez, Fatma Mujgan, Splitt, Miranda, Steenbeek, Duco, Stegmann, Alexander P.A., Stumpel, Constance T.R.M., Tanabe, Saori, Uctepe, Eyyup, Utine, G. Eda, Veenstra-Knol, Hermine E., Venkateswaran, Sunita, Vilain, Catheline, Vincent-Delorme, Catherine, Vulto-van Silfhout, Anneke T., Wheeler, Patricia, Wilson, Golder N., Wilson, Louise C., Wollnik, Bernd, Kosho, Tomoki, Wieczorek, Dagmar, Eichler, Evan, Pfundt, Rolph, de Vries, Bert B.A., Clayton-Smith, Jill, and Santen, Gijs W.E.

Published
2019
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6. Confirmation and expansion of the phenotype of the TCEAL1-related neurodevelopmental disorder

Author

Albuainain, Fatimah, primary, Shi, Yuwei, additional, Lor-Zade, Sarah, additional, Hüffmeier, Ulrike, additional, Pauly, Melissa, additional, Reis, André, additional, Faivre, Laurence, additional, Maraval, Julien, additional, Bruel, Ange-Line, additional, Them, Frédéric Tran Mau, additional, Haack, Tobias B., additional, Grasshoff, Ute, additional, Horber, Veronka, additional, Schot, Rachel, additional, van Slegtenhorst, Marjon, additional, Wilke, Martina, additional, and Barakat, Tahsin Stefan, additional

Published
2024
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7. High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one‐third of probands are minors

Author

Spiegler, Stefanie, Najm, Juliane, Liu, Jian, Gkalympoudis, Stephanie, Schröder, Winnie, Borck, Guntram, Brockmann, Knut, Elbracht, Miriam, Fauth, Christine, Ferbert, Andreas, Freudenberg, Leonie, Grasshoff, Ute, Hellenbroich, Yorck, Henn, Wolfram, Hoffjan, Sabine, Hüning, Irina, Korenke, G Christoph, Kroisel, Peter M, Kunstmann, Erdmute, Mair, Martina, Munk-Schulenburg, Susanne, Nikoubashman, Omid, Pauli, Silke, Rudnik-Schöneborn, Sabine, Sudholt, Irene, Sure, Ulrich, Tinschert, Sigrid, Wiednig, Michaela, Zoll, Barbara, Ginsberg, Mark H, and Felbor, Ute

Subjects
Stroke, Genetic Testing, Neurosciences, Rare Diseases, Brain Disorders, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Aetiology, Age at disease onset, CCM1, CCM2, CCM3, cerebral cavernous malformation, HEG1, mutation detection rate, predictive testing, Medicinal and Biomolecular Chemistry, Clinical Sciences
Abstract

Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue.

Published
2014

8. ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.

Author

Laugwitz, Lucia, Cheng, Fubo, Collins, Stephan C, Hustinx, Alexander, Navarro, Nicolas, Welsch, Simon, Cox, Helen, Hsieh, Tzung-Chien, Vijayananth, Aswinkumar, Buchert, Rebecca, Bender, Benjamin, Efthymiou, Stephanie, Murphy, David, Zafar, Faisal, Rana, Nuzhat, Grasshoff, Ute, Falb, Ruth J, Grimmel, Mona, Seibt, Annette, and Zheng, Wenxu

Subjects
INNER ear physiology, NUCLEOTIDE sequencing, NEURAL development, EMBRYONIC stem cells, SEMICIRCULAR canals, GENE targeting
Abstract

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESCs), including a knockout and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-sequencing analyses in Zscan10 −/− mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Author

Frints, Suzanna G. M., Ozanturk, Aysegul, Rodríguez Criado, Germán, Grasshoff, Ute, de Hoon, Bas, Field, Michael, Manouvrier-Hanu, Sylvie, E. Hickey, Scott, Kammoun, Molka, Gripp, Karen W., Bauer, Claudia, Schroeder, Christopher, Toutain, Annick, Mihalic Mosher, Theresa, Kelly, Benjamin J., White, Peter, Dufke, Andreas, Rentmeester, Eveline, Moon, Sungjin, Koboldt, Daniel C, van Roozendaal, Kees E. P., Hu, Hao, Haas, Stefan A., Ropers, Hans-Hilger, Murray, Lucinda, Haan, Eric, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Liebelt, Jan, Hobson, Lynne, De Rademaeker, Marjan, Geraedts, Joep, Fryns, Jean-Pierre, Vermeesch, Joris, Raynaud, Martine, Riess, Olaf, Gribnau, Joost, Katsanis, Nicholas, Devriendt, Koen, Bauer, Peter, Gecz, Jozef, Golzio, Christelle, Gontan, Cristina, and Kalscheuer, Vera M.

Published
2019
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11. Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients withZNF148mutations

Author

Szakszon, Katalin, primary, Lourenco, Charles Marques, additional, Callewaert, Bert Louis, additional, Geneviève, David, additional, Rouxel, Flavien, additional, Morin, Denis, additional, Denommé-Pichon, Anne-Sophie, additional, Vitobello, Antonio, additional, Patterson, Wesley, additional, Louie, Raymond, additional, Pinto e Vairo, Filippo, additional, Klee, Eric, additional, Kaiwar, Charu, additional, Gavrilova, Ralitza H, additional, Agre, Katherine E, additional, Jacquemont, Sebastien, additional, Khadijé, Jizi, additional, Giltay, Jacques, additional, van Gassen, Koen, additional, Merő, Gabriella, additional, Gerkes, Erica, additional, Van Bon, Bregje W, additional, Rinne, Tuula, additional, Pfundt, Rolph, additional, Brunner, Han G, additional, Caluseriu, Oana, additional, Grasshoff, Ute, additional, Kehrer, Martin, additional, Haack, Tobias B, additional, Khelifa, Melik Malek, additional, Bergmann, Anke Katharina, additional, Cueto-González, Anna Maria, additional, Martorell, Ariadna Campos, additional, Ramachandrappa, Shwetha, additional, Sawyer, Lindsey B, additional, Fasel, Pascale, additional, Braun, Dominique, additional, Isis, Atallah, additional, Superti-Furga, Andrea, additional, McNiven, Vanda, additional, Chitayat, David, additional, Ahmed, Syed Anas, additional, Brennenstuhl, Heiko, additional, Schwaibolf, Eva MC, additional, Battisti, Gladys, additional, Parmentier, Benoit, additional, and Stevens, Servi J C, additional

Published
2023
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12. PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals

Author

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

Published
2023
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13. Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Author

van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Wödl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F. J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W. Y., Chung, Brain H. Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hülya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, López-González, Vanesa, Maas, Saskia, Mancini, Grazia M. S., Marcelis, Carlo, Martinez, Francisco, Maystadt, Isabelle, McGuire, Marianne, McKee, Shane, Mehta, Sarju, Metcalfe, Kay, Milunsky, Jeff, Mizuno, Seiji, Moeschler, John B., Netzer, Christian, Ockeloen, Charlotte W., Oehl-Jaschkowitz, Barbara, Okamoto, Nobuhiko, Olminkhof, Sharon N. M., Orellana, Carmen, Pasquier, Laurent, Pottinger, Caroline, Riehmer, Vera, Robertson, Stephen P., Roifman, Maian, Rooryck, Caroline, Ropers, Fabienne G., Rosello, Monica, Ruivenkamp, Claudia A. L., Sagiroglu, Mahmut S., Sallevelt, Suzanne C. E. H., Calvo, Amparo Sanchis, Simsek-Kiper, Pelin O., Soares, Gabriela, Solaeche, Lucia, Sonmez, Fatma Mujgan, Splitt, Miranda, Steenbeek, Duco, Stegmann, Alexander P. A., Stumpel, Constance T. R. M., Tanabe, Saori, Uctepe, Eyyup, Utine, G. Eda, Veenstra-Knol, Hermine E., Venkateswaran, Sunita, Vilain, Catheline, Vincent-Delorme, Catherine, Vulto-van Silfhout, Anneke T., Wheeler, Patricia, Wilson, Golder N., Wilson, Louise C., Wollnik, Bernd, Kosho, Tomoki, Wieczorek, Dagmar, Eichler, Evan, Pfundt, Rolph, de Vries, Bert B. A., Clayton-Smith, Jill, and Santen, Gijs W. E.

Published
2019
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14. First case report of malignant peritoneal mesothelioma and oral verrucous carcinoma in a patient with a germline PTEN mutation: a combination of extremely rare diseases with probable further implications

Author

Löffler, Markus W., Steinhilber, Julia, Hilke, Franz J., Haen, Sebastian P., Bösmüller, Hans, Montes-Mojarro, Ivonne-Aidee, Bonzheim, Irina, Stäbler, Antje, Faust, Ulrike, Grasshoff, Ute, Königsrainer, Ingmar, Rammensee, Hans-Georg, Kanz, Lothar, Königsrainer, Alfred, Beckert, Stefan, Riess, Olaf, and Schroeder, Christopher

Published
2018
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15. Diagnostic genome sequencing improves diagnostic yield: a prospective single-centre study in 1000 patients with inherited eye diseases

Author

Weisschuh, Nicole, Mazzola, Pascale, Zuleger, Theresia, Schaeferhoff, Karin, Ku¨hlewein, Laura, Kortu¨m, Friederike, Witt, Dennis, Liebmann, Alexandra, Falb, Ruth, Pohl, Lisa, Reith, Milda, Stu¨hn, Lara G, Bertrand, Miriam, Mu¨ller, Amelie, Casadei, Nicolas, Kelemen, Olga, Kelbsch, Carina, Kernstock, Christoph, Richter, Paul, Sadler, Francoise, Demidov, German, Schu¨tz, Leon, Admard, Jakob, Sturm, Marc, Grasshoff, Ute, Tonagel, Felix, Heinrich, Tilman, Nasser, Fadi, Wissinger, Bernd, Ossowski, Stephan, Kohl, Susanne, Riess, Olaf, Stingl, Katarina, and Haack, Tobias B

Abstract

PurposeGenome sequencing (GS) is expected to reduce the diagnostic gap in rare disease genetics. We aimed to evaluate a scalable framework for genome-based analyses ‘beyond the exome’ in regular care of patients with inherited retinal degeneration (IRD) or inherited optic neuropathy (ION).MethodsPCR-free short-read GS was performed on 1000 consecutive probands with IRD/ION in routine diagnostics. Complementary whole-blood RNA-sequencing (RNA-seq) was done in a subset of 74 patients. An open-source bioinformatics analysis pipeline was optimised for structural variant (SV) calling and combined RNA/DNA variation interpretation.ResultsA definite genetic diagnosis was established in 57.4% of cases. For another 16.7%, variants of uncertain significance were identified in known IRD/ION genes, while the underlying genetic cause remained unresolved in 25.9%. SVs or alterations in non-coding genomic regions made up for 12.7% of the observed variants. The RNA-seq studies supported the classification of two unclear variants.ConclusionGS is feasible in clinical practice and reliably identifies causal variants in a substantial proportion of individuals. GS extends the diagnostic yield to rare non-coding variants and enables precise determination of SVs. The added diagnostic value of RNA-seq is limited by low expression levels of the major IRD disease genes in blood.

Published
2024
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16. Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148mutations

Author

Szakszon, Katalin, Lourenco, Charles Marques, Callewaert, Bert Louis, Geneviève, David, Rouxel, Flavien, Morin, Denis, Denommé-Pichon, Anne-Sophie, Vitobello, Antonio, Patterson, Wesley G, Louie, Raymond, Pinto e Vairo, Filippo, Klee, Eric, Kaiwar, Charu, Gavrilova, Ralitza H, Agre, Katherine E, Jacquemont, Sebastien, Khadijé, Jizi, Giltay, Jacques, van Gassen, Koen, Merő, Gabriella, Gerkes, Erica, Van Bon, Bregje W, Rinne, Tuula, Pfundt, Rolph, Brunner, Han G, Caluseriu, Oana, Grasshoff, Ute, Kehrer, Martin, Haack, Tobias B, Khelifa, Melik Malek, Bergmann, Anke Katharina, Cueto-González, Anna Maria, Martorell, Ariadna Campos, Ramachandrappa, Shwetha, Sawyer, Lindsey B, Fasel, Pascale, Braun, Dominique, Isis, Atallah, Superti-Furga, Andrea, McNiven, Vanda, Chitayat, David, Ahmed, Syed Anas, Brennenstuhl, Heiko, Schwaibolf, Eva MC, Battisti, Gladys, Parmentier, Benoit, and Stevens, Servi J C

Abstract

BackgroundPathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far.MethodsAs a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals.ResultsThe core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148gene. Heterozygous deletion including the entire ZNF148gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families.ConclusionThe GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term ‘GDACCF syndrome’ with ‘ZNF148-related neurodevelopmental disorder’.

Published
2024
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17. Phenotypic characterization of seven individuals with Marbach–Schaaf neurodevelopmental syndrome

Author

Marbach, Felix, primary, Lipska‐Ziętkiewicz, Beata S., additional, Knurowska, Agata, additional, Michaud, Vincent, additional, Margot, Henri, additional, Lespinasse, James, additional, Tran Mau Them, Frédéric, additional, Coubes, Christine, additional, Park, Joohyun, additional, Grosch, Sarah, additional, Roggia, Cristiana, additional, Grasshoff, Ute, additional, Kalsner, Louisa, additional, Denommé‐Pichon, Anne‐Sophie, additional, Afenjar, Alexandra, additional, Héron, Bénédicte, additional, Keren, Boris, additional, Caro, Pilar, additional, and Schaaf, Christian P., additional

Published
2022
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18. A single center experience of prenatal parent‐fetus trio exome sequencing for pregnancies with congenital anomalies

Author

Dufke, Andreas, primary, Hoopmann, Markus, additional, Waldmüller, Stephan, additional, Prodan, Natalia C., additional, Beck‐Woedl, Stefanie, additional, Grasshoff, Ute, additional, Heinrich, Tilman, additional, Riess, Angelika, additional, Kehrer, Martin, additional, Falb, Ruth J., additional, Liebmann, Alexandra, additional, Roggia, Cristiana, additional, Stampfer, Miriam, additional, Schadeck, Malou, additional, Müller, Amelie J., additional, Grimmel, Mona, additional, Stöbe, Petra, additional, Gauck, Darja, additional, Buchert‐Lo, Rebecca, additional, Baumann, Sarah, additional, Schäferhoff, Karin, additional, Bertrand, Miriam, additional, Menden, Benita, additional, Sturm, Marc, additional, Schütz, Leon, additional, Riess, Olaf, additional, Ossowski, Stephan, additional, Haack, Tobias B., additional, and Kagan, Karl Oliver, additional

Published
2022
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20. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

Author

Richard, Elodie M., Bakhtiari, Somayeh, Marsh, Ashley P.L., Kaiyrzhanov, Rauan, Wagner, Matias, Shetty, Sheetal, Pagnozzi, Alex, Nordlie, Sandra M., Guida, Brandon S., Cornejo, Patricia, Magee, Helen, Liu, James, Norton, Bethany Y., Webster, Richard I., Worgan, Lisa, Hakonarson, Hakon, Li, Jiankang, Guo, Yiran, Jain, Mahim, Blesson, Alyssa, Rodan, Lance H., Abbott, Mary-Alice, Comi, Anne, Cohen, Julie S., Alhaddad, Bader, Meitinger, Thomas, Lenz, Dominic, Ziegler, Andreas, Kotzaeridou, Urania, Brunet, Theresa, Chassevent, Anna, Smith-Hicks, Constance, Ekstein, Joseph, Weiden, Tzvi, Hahn, Andreas, Zharkinbekova, Nazira, Turnpenny, Peter, Tucci, Arianna, Yelton, Melissa, Horvath, Rita, Gungor, Serdal, Hiz, Semra, Oktay, Yavuz, Lochmuller, Hanns, Zollino, Marcella, Morleo, Manuela, Marangi, Giuseppe, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Amenta, Simona, Husain, Ralf A., Grossmann, Benita, Rapp, Marion, Steen, Claudia, Marquardt, Iris, Grimmel, Mona, Grasshoff, Ute, Korenke, G. Christoph, Owczarek-Lipska, Marta, Neidhardt, John, Radio, Francesca Clementina, Mancini, Cecilia, Claps Sepulveda, Dianela Judith, McWalter, Kirsty, Begtrup, Amber, Crunk, Amy, Guillen Sacoto, Maria J., Person, Richard, Schnur, Rhonda E., Mancardi, Maria Margherita, Kreuder, Florian, Striano, Pasquale, Zara, Federico, Chung, Wendy K., Marks, Warren A., van Eyk, Clare L., Webber, Dani L., Corbett, Mark A., Harper, Kelly, Berry, Jesia G., MacLennan, Alastair H., Gecz, Jozef, Tartaglia, Marco, Salpietro, Vincenzo, Christodoulou, John, Kaslin, Jan, Padilla-Lopez, Sergio, Bilguvar, Kaya, Munchau, Alexander, Ahmed, Zubair M., Hufnagel, Robert B., Fahey, Michael C., Maroofian, Reza, Houlden, Henry, Sticht, Heinrich, Mane, Shrikant M., Rad, Aboulfazl, Vona, Barbara, Jin, Sheng Chih, Haack, Tobias B., Makowski, Christine, Hirsch, Yoel, Riazuddin, Saima, and Kruer, Michael C.

Published
2021
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22. Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex.

Author

Falb, Ruth J., Müller, Amelie J., Klein, Wolfram, Grimmel, Mona, Grasshoff, Ute, Spranger, Stephanie, Stöbe, Petra, Gauck, Darja, Kuechler, Alma, Dikow, Nicola, Schwaibold, Eva M. C., Schmidt, Christoph, Averdunk, Luisa, Buchert, Rebecca, Heinrich, Tilman, Prodan, Natalia, Park, Joohyun, Kehrer, Martin, Sturm, Marc, and Kelemen, Olga

Abstract

Background Fetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved. Methods We performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature. Results We identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene (KIF21A) was found. Conclusion Our study underlines the broad locus heterogeneity of FA with well-established and atypical genotype-phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets. [ABSTRACT FROM AUTHOR]

Published
2023
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23. Bi-allelic loss-of-function variants inKIF21Acause severe fetal akinesia with arthrogryposis multiplex

Author

Falb, Ruth J, primary, Müller, Amelie J, additional, Klein, Wolfram, additional, Grimmel, Mona, additional, Grasshoff, Ute, additional, Spranger, Stephanie, additional, Stöbe, Petra, additional, Gauck, Darja, additional, Kuechler, Alma, additional, Dikow, Nicola, additional, Schwaibold, Eva M C, additional, Schmidt, Christoph, additional, Averdunk, Luisa, additional, Buchert, Rebecca, additional, Heinrich, Tilman, additional, Prodan, Natalia, additional, Park, Joohyun, additional, Kehrer, Martin, additional, Sturm, Marc, additional, Kelemen, Olga, additional, Hartmann, Silke, additional, Horn, Denise, additional, Emmerich, Dirk, additional, Hirt, Nina, additional, Neumann, Armin, additional, Kristiansen, Glen, additional, Gembruch, Ulrich, additional, Haen, Susanne, additional, Siebert, Reiner, additional, Hentze, Sabine, additional, Hoopmann, Markus, additional, Ossowski, Stephan, additional, Waldmüller, Stephan, additional, Beck-Wödl, Stefanie, additional, Gläser, Dieter, additional, Tekesin, Ismail, additional, Distelmaier, Felix, additional, Riess, Olaf, additional, Kagan, Karl-Oliver, additional, Dufke, Andreas, additional, and Haack, Tobias B, additional

Published
2021
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24. Isolated cytokine‐enriched pericardial effusion: A likely key feature for Aymé‐Gripp syndrome

Author

König, Anna‐Lina, primary, Sabir, Hemmen, additional, Stritzek, Brigitte, additional, Gembruch, Ulrich, additional, Herberg, Ulrike, additional, Bertrand, Miriam, additional, Grasshoff, Ute, additional, Wiegand, Gesa, additional, Wiechers, Cornelia, additional, Bernis, Eugenia, additional, Reutter, Heiko, additional, and Müller, Andreas, additional

Published
2021
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25. Severe presentation of WDR62 mutation: Is there a role for modifying genetic factors?

Author

Poulton, Cathryn J., Schot, Rachel, Seufert, Katja, Lequin, Maarten H., Accogli, Andrea, Dʼ Annunzio, Giuseppe, Villard, Laurent, Philip, Nicole, de Coo, René, Catsman-Berrevoets, Coriene, Grasshoff, Ute, Kattentidt-Mouravieva, Anja, Calf, Hans, de Vreugt-Gronloh, Erika, van Unen, Leontine, Verheijen, Frans W., Galjart, Niels, Morris-Rosendahl, Deborah J., and Mancini, Grazia M. S.

Published
2014
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26. The Role of Neuroimaging and Genetic Analysis in the Diagnosis of Children With Cerebral Palsy

Author

Horber, Veronka, Grasshoff, Ute, Sellier, Elodie, Arnaud, Catherine, Krägeloh-Mann, Ingeborg, and Himmelmann, Kate

Subjects
cerebral palsy, Neurology, classification, diagnosis, Perspective, magnetic resonance imaging, genetic analysis
Abstract

Cerebral magnetic resonance imaging (MRI) is considered an important tool in the assessment of a child with cerebral palsy (CP), as it is abnormal in more than 80% of children with CP, disclosing the pathogenic pattern responsible for the neurological condition. MRI, therefore, is recommended as the first diagnostic step after medical history taking and neurological examination. With the advances in genetic diagnostics, the genetic contribution to CP is increasingly discussed, and the question arises about the role of genetic testing in the diagnosis of cerebral palsy. The paper gives an overview on genetic findings reported in CP, which are discussed with respect to the underlying brain pathology according to neuroimaging findings. Surveillance of Cerebral Palsy in Europe (SCPE) classifies neuroimaging findings in CP into five categories, which help to stratify decisions concerning genetic testing. Predominant white and gray matter injuries are by far predominant (accounting for around 50 and 20% of the findings). They are considered to be acquired. Here, predisposing genetic factors may play a role to increase vulnerability (and should especially be considered, when family history is positive and/or causative external factors are missing). In maldevelopments and normal findings (around 11% each), monogenic causes are more likely, and thus, genetic testing is clearly recommended. In the miscellaneous category, the precise nature of the MRI finding has to be considered as it could indicate a genetic origin.

Published
2021

29. Bi-allelic loss-of-function variants in KIF21Acause severe fetal akinesia with arthrogryposis multiplex

Author

Falb, Ruth J, Mu¨ller, Amelie J, Klein, Wolfram, Grimmel, Mona, Grasshoff, Ute, Spranger, Stephanie, Sto¨be, Petra, Gauck, Darja, Kuechler, Alma, Dikow, Nicola, Schwaibold, Eva M C, Schmidt, Christoph, Averdunk, Luisa, Buchert, Rebecca, Heinrich, Tilman, Prodan, Natalia, Park, Joohyun, Kehrer, Martin, Sturm, Marc, Kelemen, Olga, Hartmann, Silke, Horn, Denise, Emmerich, Dirk, Hirt, Nina, Neumann, Armin, Kristiansen, Glen, Gembruch, Ulrich, Haen, Susanne, Siebert, Reiner, Hentze, Sabine, Hoopmann, Markus, Ossowski, Stephan, Waldmu¨ller, Stephan, Beck-Wo¨dl, Stefanie, Gla¨ser, Dieter, Tekesin, Ismail, Distelmaier, Felix, Riess, Olaf, Kagan, Karl-Oliver, Dufke, Andreas, and Haack, Tobias B

Abstract

BackgroundFetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved.MethodsWe performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature.ResultsWe identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21Agene (KIF21A) was found.ConclusionOur study underlines the broad locus heterogeneity of FA with well-established and atypical genotype–phenotype associations. We describe KIF21Aas a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets.

Published
2023
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33. A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL

Author

Haemmerling, Susanne, Behnisch, Wolfgang, Doerks, Tobias, Korbel, Jan O., Bork, Peer, Moog, Ute, Hentze, Sabine, Grasshoff, Ute, Bonin, Michael, Rie, Olaf, Janssen, Johannes W. G., Jauch, Anna, Bartram, Claus R., Reinhardt, Dirk, Koch, Karin A., Bandapalli, Obul R., and Kulozik, Andreas E.

Published
2012
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34. Phenotypic spectrum associated with CASK loss-of-function mutations

Author

Moog, Ute, Kutsche, Kerstin, Kortüm, Fanny, Chilian, Bettina, Bierhals, Tatjana, Apeshiotis, Neophytos, Balg, Stefanie, Chassaing, Nicolas, Coubes, Christine, Das, Soma, Engels, Hartmut, Van Esch, Hilde, Grasshoff, Ute, Heise, Marisol, Isidor, Bertrand, Jarvis, Joanna, Koehler, Udo, Martin, Thomas, Oehl-Jaschkowitz, Barbara, Ortibus, Els, Pilz, Daniela T, Prabhakar, Prab, Rappold, Gudrun, Rau, Isabella, Rettenberger, Günther, Schlüter, Gregor, Scott, Richard H, Shoukier, Moonef, Wohlleber, Eva, Zirn, Birgit, Dobyns, William B, and Uyanik, Gökhan

Published
2011
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35. Clinico‐Genetic, Imaging and Molecular Delineation of COQ8A‐Ataxia: A Multicenter Study of 59 Patients

Author

Traschütz, Andreas, primary, Schirinzi, Tommaso, additional, Laugwitz, Lucia, additional, Murray, Nathan H., additional, Bingman, Craig A., additional, Reich, Selina, additional, Kern, Jan, additional, Heinzmann, Anna, additional, Vasco, Gessica, additional, Bertini, Enrico, additional, Zanni, Ginevra, additional, Durr, Alexandra, additional, Magri, Stefania, additional, Taroni, Franco, additional, Malandrini, Alessandro, additional, Baets, Jonathan, additional, de Jonghe, Peter, additional, de Ridder, Willem, additional, Bereau, Matthieu, additional, Demuth, Stephanie, additional, Ganos, Christos, additional, Basak, A. Nazli, additional, Hanagasi, Hasmet, additional, Kurul, Semra Hiz, additional, Bender, Benjamin, additional, Schöls, Ludger, additional, Grasshoff, Ute, additional, Klopstock, Thomas, additional, Horvath, Rita, additional, van de Warrenburg, Bart, additional, Burglen, Lydie, additional, Rougeot, Christelle, additional, Ewenczyk, Claire, additional, Koenig, Michel, additional, Santorelli, Filippo M., additional, Anheim, Mathieu, additional, Munhoz, Renato P., additional, Haack, Tobias, additional, Distelmaier, Felix, additional, Pagliarini, David J., additional, Puccio, Hélène, additional, and Synofzik, Matthis, additional

Published
2020
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37. Mutations in MEF2C from the 5q14.3q15 Microdeletion Syndrome Region Are a Frequent Cause of Severe Mental Retardation and Diminish MECP2 and CDKL5 Expression

Author

Zweier, Markus, Gregor, Anne, Zweier, Christiane, Engels, Hartmut, Sticht, Heinrich, Wohlleber, Eva, Bijlsma, Emilia K., Holder, Susan E., Zenker, Martin, Rossier, Eva, Grasshoff, Ute, Johnson, Diana S., Robertson, Lisa, Firth, Helen V., Kraus, Cornelia, Ekici, Arif B., Reis, André, and Rauch, Anita

Published
2010
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38. Molecular Karyotyping of Patients with Unexplained Mental Retardation by SNP Arrays: A Multicenter Study

Author

McMullan, Dominic J., Bonin, Michael, Hehir-Kwa, Jayne Y., de Vries, Bert B.A., Dufke, Andreas, Rattenberry, Eleanor, Steehouwer, Marloes, Moruz, Luminita, Pfundt, Rolph, de Leeuw, Nicole, Riess, Angelika, Altug-Teber, Özge, Enders, Herbert, Singer, Sylke, Grasshoff, Ute, Walter, Michael, Walker, Judith M., Lamb, Catherine V., Val Davison, E., Brueton, Louise, Riess, Olaf, and Veltman, Joris A.

Published
2009
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39. Clinico-genetic, imaging and molecular delineation of COQ8A-ataxia: a multicenter study of 59 patients

Author

Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Traschuetz, Andreas; Schirinzi, Tommaso; Laugwitz, Lucia; Murray, Nathan H.; Bingman, Craig A.; Reich, Selina; Kern, Jan; Heinzmann, Anna; Vasco, Gessica; Bertini, Enrico; Zanni, Ginevra; Durr, Alexandra; Magri, Stefania; Taroni, Franco; Malandrini, Alessandro; Baets, Jonathan; de Jonghe, Peter; de Ridder, Willem; Bereau, Matthieu; Demuth, Stephanie; Ganos, Christos; Hanagasi, Hasmet; Kurul, Semra Hız; Bender, Benjamin; Schoels, Ludger; Grasshoff, Ute; Klopstock, Thomas; Horvath, Rita; van de Warrenburg, Bart; Burglen, Lydie; Rougeot, Christelle; Ewenczyk, Claire; Koenig, Michel; Santorelli, Filippo M.; Anheim, Mathieu; Munhoz, Renato P.; Haack, Tobias; Distelmaier, Felix; Pagliarini, David J.; Puccio, Helene; Synofzik, Matthis, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Traschuetz, Andreas; Schirinzi, Tommaso; Laugwitz, Lucia; Murray, Nathan H.; Bingman, Craig A.; Reich, Selina; Kern, Jan; Heinzmann, Anna; Vasco, Gessica; Bertini, Enrico; Zanni, Ginevra; Durr, Alexandra; Magri, Stefania; Taroni, Franco; Malandrini, Alessandro; Baets, Jonathan; de Jonghe, Peter; de Ridder, Willem; Bereau, Matthieu; Demuth, Stephanie; Ganos, Christos; Hanagasi, Hasmet; Kurul, Semra Hız; Bender, Benjamin; Schoels, Ludger; Grasshoff, Ute; Klopstock, Thomas; Horvath, Rita; van de Warrenburg, Bart; Burglen, Lydie; Rougeot, Christelle; Ewenczyk, Claire; Koenig, Michel; Santorelli, Filippo M.; Anheim, Mathieu; Munhoz, Renato P.; Haack, Tobias; Distelmaier, Felix; Pagliarini, David J.; Puccio, Helene; Synofzik, Matthis, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Objective: to foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that >= 48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: this study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia., European Union (European Union); Horizon 2020; European Union's Horizon 2020 Research and Innovation Program by the BMBF, E-Rare-3 network PREPARE; European Union's Horizon 2020 Research and Innovation Program, Solve-RD; German Bundesministerium fur Bildung und Forschung (BMBF), in der Systemmedizin "mitOmics; University of Tubingen, Medical Faculty, for the Clinician Scientist; Italian Ministry of Health; German Research Foundation/Deutsche Forschungsgemeinschaft; NIH; NSF; Wellcome Trust Investigator; ; Medical Research Council (UK); European Research Council (ERC); Wellcome Trust Pathfinder Scheme; Newton Fund; Senior Clinical Researcher mandate of the Research Fund - Flanders (FWO); ZonMW, Hersenstichting, Gossweiler Foundation; Radboud University Medical Centre; VolkswagenStiftung (Freigeist Fellowship; Deutsche Forschungsgemeinschaft; German Parkinson Society and Actelion Pharmaceuticals; Italian Ministry of Health Ricerca Finalizzata Suna and İnan Kıraç Foundation and Koç University School of Medicine

Published
2020

40. Isolated cytokine‐enriched pericardial effusion: A likely key feature for Aymé‐Gripp syndrome.

Author

König, Anna‐Lina, Sabir, Hemmen, Strizek, Brigitte, Gembruch, Ulrich, Herberg, Ulrike, Bertrand, Miriam, Grasshoff, Ute, Wiegand, Gesa, Wiechers, Cornelia, Bernis, Eugenia, Reutter, Heiko, and Müller, Andreas

Abstract

Aymé‐Gripp syndrome is a multisystemic disorder caused by a heterozygous variation in the MAF gene (OMIM*177075). Key features are congenital cataracts, sensorineural hearing loss, and a characteristic facial appearance. In a proportion of individuals, pericardial effusion or pericarditis has been reported as part of the phenotypic spectrum. In the present case, a large persistent cytokine‐enriched pericardial effusion was the main pre‐ and postnatal symptom that led to the clinical and later molecular diagnosis of Aymé‐Gripp syndrome. In the postnatal course, the typical Aymé‐Gripp syndrome‐associated features bilateral cataracts and hearing loss were diagnosed. We propose that activating dominant variants in the cytokine‐modulating transcription factor c‐MAF causes cytokine‐enriched pericardial effusions possibly representing a key feature of Aymé‐Gripp syndrome. [ABSTRACT FROM AUTHOR]

Published
2022
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41. Transgenic rat model of Huntingtonʼs disease

Author

von Hörsten, Stephan, Schmitt, Ina, Nguyen, Huu Phuc, Holzmann, Carsten, Schmidt, Thorsten, Walther, Thomas, Bader, Michael, Pabst, Reinhard, Kobbe, Philipp, Krotova, Jana, Stiller, Detlef, Kask, Ants, Vaarmann, Annika, Rathke-Hartlieb, Silvia, Schulz, Jörg B., Grasshoff, Ute, Bauer, Ingrid, Menezes Vieira-Saecker, Ana Maria, Paul, Martin, Jones, Lesley, Lindenberg, Katrin S., Landwehrmeyer, Bernhard, Bauer, Andreas, Li, Xiao-Jiang, and Riess, Olaf

Published
2003

42. De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy

Author

Park, Joohyun, primary, Flores, Bianca R, additional, Scherer, Katalin, additional, Kuepper, Hanna, additional, Rossi, Mari, additional, Rupprich, Katrin, additional, Rautenberg, Maren, additional, Deininger, Natalie, additional, Weichselbaum, Annette, additional, Grimm, Alexander, additional, Sturm, Marc, additional, Grasshoff, Ute, additional, Delpire, Eric, additional, and Haack, Tobias B, additional

Published
2019
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43. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Author

Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), van der Sluijs, Pleuntje J.; Jansen, Sandra; Vergano, Samantha A.; Adachi-Fukuda, Miho; Alanay, Yasemin; AlKindy, Adila; Baban, Anwar; Bayat, Allan; Beck-Woedl, Stefanie; Berry, Katherine; Bijlsma, Emilia K.; Bok, Levinus A.; Brouwer, Alwin F. J.; van der Burgt, Ineke; Campeau, Philippe M.; Canham, Natalie; Chrzanowska, Krystyna; Chu, Yoyo W. Y.; Chung, Brain H. Y.; Dahan, Karin; De Rademaeker, Marjan; Destree, Anne; Dudding-Byth, Tracy; Earl, Rachel; Elçioğlu, Nursel; Elias, Ellen R.; Fagerberg, Christina; Gardham, Alice; Gener, Blanca; Gerkes, Erica H.; Grasshoff, Ute; van Haeringen, Arie; Heitink, Karin R.; Herkert, Johanna C.; den Hollander, Nicolette S.; Horn, Denise; Hunt, David; Kant, Sarina G.; Kato, Mitsuhiro; Kersseboom, Rogier; Kılıç, Esra; Krajewska-Walasek, Malgorzata; Lammers, Kylin; Laulund, Lone W.; Lederer, Damien; Lees, Melissa; Lopez-Gonzalez, Vanesa; Maas, Saskia; Mancini, Grazia M. S.; Marcelis, Carlo; Martinez, Francisco; Maystadt, Isabelle; McGuire, Marianne; McKee, Shane; Mehta, Sarju; Metcalfe, Kay; Milunsky, Jeff; Mizuno, Seiji; Moeschler, John B.; Netzer, Christian; Ockeloen, Charlotte W.; Oehl-Jaschkowitz, Barbara; Okamoto, Nobuhiko; Olminkhof, Sharon N. M.; Orellana, Carmen; Pasquier, Laurent; Pottinger, Caroline; Riehmer, Vera; Robertson, Stephen P.; Roifman, Maian; Rooryck, Caroline; Ropers, Fabienne G.; Rosello, Monica; Ruivenkamp, Claudia A. L.; Sağıroğlu, Mahmut S.; Sallevelt, Suzanne C. E. H.; Sanchis Calvo, Amparo; Şimşek-Kiper, Pelin O.; Soares, Gabriela; Solaeche, Lucia; Sönmez, Fatma Müjgan; Splitt, Miranda; Steenbeek, Duco; Stegmann, Alexander P. A.; Stumpel, Constance T. R. M.; Tanabe, Saori; Üçtepe, Eyyüp; Utine, G. Eda; Veenstra-Knol, Hermine E.; Venkateswaran, Sunita; Vilain, Catheline; Vincent-Delorme, Catherine; Vulto-van Silfhout, Anneke T.; Wheeler, Patricia; Wilson, Golder N.; Wilson, Louise C.; Wollnik, Bernd; Kosho, Tomoki; Wieczorek, Dagmar; Eichler, Evan; Pfundt, Rolph; de Vries, Bert B. A.; Clayton-Smith, Jill; S, School of Medicine, Department of Medical Genetics, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), van der Sluijs, Pleuntje J.; Jansen, Sandra; Vergano, Samantha A.; Adachi-Fukuda, Miho; Alanay, Yasemin; AlKindy, Adila; Baban, Anwar; Bayat, Allan; Beck-Woedl, Stefanie; Berry, Katherine; Bijlsma, Emilia K.; Bok, Levinus A.; Brouwer, Alwin F. J.; van der Burgt, Ineke; Campeau, Philippe M.; Canham, Natalie; Chrzanowska, Krystyna; Chu, Yoyo W. Y.; Chung, Brain H. Y.; Dahan, Karin; De Rademaeker, Marjan; Destree, Anne; Dudding-Byth, Tracy; Earl, Rachel; Elçioğlu, Nursel; Elias, Ellen R.; Fagerberg, Christina; Gardham, Alice; Gener, Blanca; Gerkes, Erica H.; Grasshoff, Ute; van Haeringen, Arie; Heitink, Karin R.; Herkert, Johanna C.; den Hollander, Nicolette S.; Horn, Denise; Hunt, David; Kant, Sarina G.; Kato, Mitsuhiro; Kersseboom, Rogier; Kılıç, Esra; Krajewska-Walasek, Malgorzata; Lammers, Kylin; Laulund, Lone W.; Lederer, Damien; Lees, Melissa; Lopez-Gonzalez, Vanesa; Maas, Saskia; Mancini, Grazia M. S.; Marcelis, Carlo; Martinez, Francisco; Maystadt, Isabelle; McGuire, Marianne; McKee, Shane; Mehta, Sarju; Metcalfe, Kay; Milunsky, Jeff; Mizuno, Seiji; Moeschler, John B.; Netzer, Christian; Ockeloen, Charlotte W.; Oehl-Jaschkowitz, Barbara; Okamoto, Nobuhiko; Olminkhof, Sharon N. M.; Orellana, Carmen; Pasquier, Laurent; Pottinger, Caroline; Riehmer, Vera; Robertson, Stephen P.; Roifman, Maian; Rooryck, Caroline; Ropers, Fabienne G.; Rosello, Monica; Ruivenkamp, Claudia A. L.; Sağıroğlu, Mahmut S.; Sallevelt, Suzanne C. E. H.; Sanchis Calvo, Amparo; Şimşek-Kiper, Pelin O.; Soares, Gabriela; Solaeche, Lucia; Sönmez, Fatma Müjgan; Splitt, Miranda; Steenbeek, Duco; Stegmann, Alexander P. A.; Stumpel, Constance T. R. M.; Tanabe, Saori; Üçtepe, Eyyüp; Utine, G. Eda; Veenstra-Knol, Hermine E.; Venkateswaran, Sunita; Vilain, Catheline; Vincent-Delorme, Catherine; Vulto-van Silfhout, Anneke T.; Wheeler, Patricia; Wilson, Golder N.; Wilson, Louise C.; Wollnik, Bernd; Kosho, Tomoki; Wieczorek, Dagmar; Eichler, Evan; Pfundt, Rolph; de Vries, Bert B. A.; Clayton-Smith, Jill; S, School of Medicine, and Department of Medical Genetics

Abstract

Purpose: pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: there are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., Netherlands Organisation for Health Research and Development

Published
2019

44. The ARID1B spectrum in 143 patients:from nonsyndromic intellectual disability to Coffin–Siris syndrome

Author

van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Wödl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F.J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W.Y., Chung, Brain H.Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hülya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, López-González, Vanesa, Maas, Saskia, Mancini, Grazia M.S., van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Wödl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F.J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W.Y., Chung, Brain H.Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hülya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, López-González, Vanesa, Maas, Saskia, and Mancini, Grazia M.S.

Abstract

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

Published
2019

45. Correction:The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome (Genetics in Medicine, (2019), 21, 6, (1295-1307), 10.1038/s41436-018-0330-z)

Author

van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Wödl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F.J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W.Y., Chung, Brain H.Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hülya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, López-González, Vanesa, Maas, Saskia, Mancini, Grazia M.S., van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Wödl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F.J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W.Y., Chung, Brain H.Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hülya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, López-González, Vanesa, Maas, Saskia, and Mancini, Grazia M.S.

Abstract

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

46. Additional file 1: of First case report of malignant peritoneal mesothelioma and oral verrucous carcinoma in a patient with a germline PTEN mutation: a combination of extremely rare diseases with probable further implications

Author

Löffler, Markus, Steinhilber, Julia, Hilke, Franz, Haen, Sebastian, Bösmüller, Hans, Ivonne-Aidee Montes-Mojarro, Bonzheim, Irina, Stäbler, Antje, Faust, Ulrike, Grasshoff, Ute, Königsrainer, Ingmar, Hans-Georg Rammensee, Kanz, Lothar, Königsrainer, Alfred, Beckert, Stefan, Riess, Olaf, and Schroeder, Christopher

Abstract

Further details on materials and methods used for this case study are provided as a supplement. (PDF 101 kb)

Published
2018
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47. Novel HIVEP2 Variants in Patients with Intellectual Disability

Author

Park, Joohyun, primary, Colombo, Roberto, additional, Schäferhoff, Karin, additional, Janiri, Luigi, additional, Grimmel, Mona, additional, Sturm, Marc, additional, Grasshoff, Ute, additional, Dufke, Andreas, additional, Haack, Tobias B., additional, and Kehrer, Martin, additional

Published
2019
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48. De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.

Author

Joohyun Park, Flores, Bianca R., Scherer, Katalin, Kuepper, Hanna, Rossi, Mari, Rupprich, Katrin, Rautenberg, Maren, Deininger, Natalie, Weichselbaum, Annette, Grimm, Alexander, Sturm, Marc, Grasshoff, Ute, Delpire, Eric, and Haack, Tobias B.

Abstract

Background Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT. Methods We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes. Results We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes. Conclusion Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy. [ABSTRACT FROM AUTHOR]

Published
2020
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50. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Author

Frints, Suzanna G. M., primary, Ozanturk, Aysegul, additional, Rodríguez Criado, Germán, additional, Grasshoff, Ute, additional, de Hoon, Bas, additional, Field, Michael, additional, Manouvrier-Hanu, Sylvie, additional, E. Hickey, Scott, additional, Kammoun, Molka, additional, Gripp, Karen W., additional, Bauer, Claudia, additional, Schroeder, Christopher, additional, Toutain, Annick, additional, Mihalic Mosher, Theresa, additional, Kelly, Benjamin J., additional, White, Peter, additional, Dufke, Andreas, additional, Rentmeester, Eveline, additional, Moon, Sungjin, additional, Koboldt, Daniel C, additional, van Roozendaal, Kees E. P., additional, Hu, Hao, additional, Haas, Stefan A., additional, Ropers, Hans-Hilger, additional, Murray, Lucinda, additional, Haan, Eric, additional, Shaw, Marie, additional, Carroll, Renee, additional, Friend, Kathryn, additional, Liebelt, Jan, additional, Hobson, Lynne, additional, De Rademaeker, Marjan, additional, Geraedts, Joep, additional, Fryns, Jean-Pierre, additional, Vermeesch, Joris, additional, Raynaud, Martine, additional, Riess, Olaf, additional, Gribnau, Joost, additional, Katsanis, Nicholas, additional, Devriendt, Koen, additional, Bauer, Peter, additional, Gecz, Jozef, additional, Golzio, Christelle, additional, Gontan, Cristina, additional, and Kalscheuer, Vera M., additional

Published
2018
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