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1. Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings

Author

Schmidt, Axel, Danyel, Magdalena, Grundmann, Kathrin, Brunet, Theresa, Klinkhammer, Hannah, Hsieh, Tzung-Chien, Engels, Hartmut, Peters, Sophia, Knaus, Alexej, Moosa, Shahida, Averdunk, Luisa, Boschann, Felix, Sczakiel, Henrike Lisa, Schwartzmann, Sarina, Mensah, Martin Atta, Pantel, Jean Tori, Holtgrewe, Manuel, Bösch, Annemarie, Weiß, Claudia, Weinhold, Natalie, Suter, Aude-Annick, Stoltenburg, Corinna, Neugebauer, Julia, Kallinich, Tillmann, Kaindl, Angela M., Holzhauer, Susanne, Bührer, Christoph, Bufler, Philip, Kornak, Uwe, Ott, Claus-Eric, Schülke, Markus, Nguyen, Hoa Huu Phuc, Hoffjan, Sabine, Grasemann, Corinna, Rothoeft, Tobias, Brinkmann, Folke, Matar, Nora, Sivalingam, Sugirthan, Perne, Claudia, Mangold, Elisabeth, Kreiss, Martina, Cremer, Kirsten, Betz, Regina C., Mücke, Martin, Grigull, Lorenz, Klockgether, Thomas, Spier, Isabel, Heimbach, André, Bender, Tim, Brand, Fabian, Stieber, Christiane, Morawiec, Alexandra Marzena, Karakostas, Pantelis, Schäfer, Valentin S., Bernsen, Sarah, Weydt, Patrick, Castro-Gomez, Sergio, Aziz, Ahmad, Grobe-Einsler, Marcus, Kimmich, Okka, Kobeleva, Xenia, Önder, Demet, Lesmann, Hellen, Kumar, Sheetal, Tacik, Pawel, Basin, Meghna Ahuja, Incardona, Pietro, Lee-Kirsch, Min Ae, Berner, Reinhard, Schuetz, Catharina, Körholz, Julia, Kretschmer, Tanita, Di Donato, Nataliya, Schröck, Evelin, Heinen, André, Reuner, Ulrike, Hanßke, Amalia-Mihaela, Kaiser, Frank J., Manka, Eva, Munteanu, Martin, Kuechler, Alma, Cordula, Kiewert, Hirtz, Raphael, Schlapakow, Elena, Schlein, Christian, Lisfeld, Jasmin, Kubisch, Christian, Herget, Theresia, Hempel, Maja, Weiler-Normann, Christina, Ullrich, Kurt, Schramm, Christoph, Rudolph, Cornelia, Rillig, Franziska, Groffmann, Maximilian, Muntau, Ania, Tibelius, Alexandra, Schwaibold, Eva M. C., Schaaf, Christian P., Zawada, Michal, Kaufmann, Lilian, Hinderhofer, Katrin, Okun, Pamela M., Kotzaeridou, Urania, Hoffmann, Georg F., Choukair, Daniela, Bettendorf, Markus, Spielmann, Malte, Ripke, Annekatrin, Pauly, Martje, Münchau, Alexander, Lohmann, Katja, Hüning, Irina, Hanker, Britta, Bäumer, Tobias, Herzog, Rebecca, Hellenbroich, Yorck, Westphal, Dominik S., Strom, Tim, Kovacs, Reka, Riedhammer, Korbinian M., Mayerhanser, Katharina, Graf, Elisabeth, Brugger, Melanie, Hoefele, Julia, Oexle, Konrad, Mirza-Schreiber, Nazanin, Berutti, Riccardo, Schatz, Ulrich, Krenn, Martin, Makowski, Christine, Weigand, Heike, Schröder, Sebastian, Rohlfs, Meino, Vill, Katharina, Hauck, Fabian, Borggraefe, Ingo, Müller-Felber, Wolfgang, Kurth, Ingo, Elbracht, Miriam, Knopp, Cordula, Begemann, Matthias, Kraft, Florian, Lemke, Johannes R., Hentschel, Julia, Platzer, Konrad, Strehlow, Vincent, Abou Jamra, Rami, Kehrer, Martin, Demidov, German, Beck-Wödl, Stefanie, Graessner, Holm, Sturm, Marc, Zeltner, Lena, Schöls, Ludger J., Magg, Janine, Bevot, Andrea, Kehrer, Christiane, Kaiser, Nadja, Turro, Ernest, Horn, Denise, Grüters-Kieslich, Annette, Klein, Christoph, Mundlos, Stefan, Nöthen, Markus, Riess, Olaf, Meitinger, Thomas, Krude, Heiko, Krawitz, Peter M., Haack, Tobias, Ehmke, Nadja, and Wagner, Matias

Published
2024
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3. Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

Author

Worthmann, Anna, Ridder, Julius, Piel, Sharlaine Y. L., Evangelakos, Ioannis, Musfeldt, Melina, Voß, Hannah, O’Farrell, Marie, Fischer, Alexander W., Adak, Sangeeta, Sundd, Monica, Siffeti, Hasibullah, Haumann, Friederike, Kloth, Katja, Bierhals, Tatjana, Heine, Markus, Pertzborn, Paul, Pauly, Mira, Scholz, Julia-Josefine, Kundu, Suman, Fuh, Marceline M., Neu, Axel, Tödter, Klaus, Hempel, Maja, Knippschild, Uwe, Semenkovich, Clay F., Schlüter, Hartmut, Heeren, Joerg, Scheja, Ludger, Kubisch, Christian, and Schlein, Christian

Published
2024
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4. Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation.

Author

von Elsner, Leonie, Chai, Guoliang, Schneeberger, Pauline E, Harms, Frederike L, Casar, Christian, Qi, Minyue, Alawi, Malik, Abdel-Salam, Ghada MH, Zaki, Maha S, Arndt, Florian, Yang, Xiaoxu, Stanley, Valentina, Hempel, Maja, Gleeson, Joseph G, and Kutsche, Kerstin

Subjects
Brain Disorders, Neurosciences, Clinical Research, Intellectual and Developmental Disabilities (IDD), Rare Diseases, Genetics, Aetiology, 2.1 Biological and endogenous factors, DNA-Binding Proteins, Growth Disorders, Humans, Intellectual Disability, Membrane Proteins, Microcephaly, Neurodevelopmental Disorders, Nuclear Proteins, RNA Splice Sites, RNA-Binding Proteins, Repressor Proteins, exome sequencing, homozygous, major spliceosome, splicing, intellectual disability, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5' and 3' splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated Patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of Patients 1 and 2. In a heterologous expression system, the p.Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5' and 3' splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions.

Published
2022

5. Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease

Author

Hammann, Nicole, Lenz, Dominic, Baric, Ivo, Crushell, Ellen, Vici, Carlo Dionisi, Distelmaier, Felix, Feillet, Francois, Freisinger, Peter, Hempel, Maja, Khoreva, Anna L., Laass, Martin W., Lacassie, Yves, Lainka, Elke, Larson-Nath, Catherine, Li, Zhongdie, Lipiński, Patryk, Lurz, Eberhard, Mégarbané, André, Nobre, Susana, Olivieri, Giorgia, Peters, Bianca, Prontera, Paolo, Schlieben, Lea D., Seroogy, Christine M., Sobacchi, Cristina, Suzuki, Shigeru, Tran, Christel, Vockley, Jerry, Wang, Jian-She, Wagner, Matias, Prokisch, Holger, Garbade, Sven F., Kölker, Stefan, Hoffmann, Georg F., and Staufner, Christian

Published
2024
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6. Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi DP, Huber, Hannes, Murry, Jaclyn B, Abramson, Jeff, Althoff, Thorsten, Banka, Siddharth, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J, Berland, Siren, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A, Braathen, Geir Julius, Busk, Øyvind L, Chenbhanich, Jirat, Denecke, Jonas, Escobar, Luis F, Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A, Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Le Guyader, Gwenael, Ljungblad, Ulf W, Brenman, Leslie Manace, Martinez-Agosto, Julian A, Might, Matthew, Miller, David T, Minks, Kelly Q, Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F, Parant, John M, Prescott, Trine, Rajabi, Farrah, Randrianaivo, Hanitra, Reiter, Simone F, Schuurs-Hoeijmakers, Janneke, Shieh, Perry B, Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander PA, Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H, Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Kreienkamp, Hans-Jürgen, and Lessel, Davor

Subjects
Biological Sciences, Genetics, Pediatric, Clinical Research, Mental Health, Prevention, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, Animals, Biomarkers, Gene Expression, Gene Knockdown Techniques, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, HEK293 Cells, Humans, Immunohistochemistry, Mutation, Neurodevelopmental Disorders, Phenotype, RNA Helicases, Zebrafish, Clinical Sciences
Abstract

BackgroundWe aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder.MethodsClinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.ResultsWe identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.ConclusionsOur study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Published
2021

8. Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders

Author

Duncan, Anna R, Polovitskaya, Maya M, Gaitán-Peñas, Héctor, Bertelli, Sara, VanNoy, Grace E, Grant, Patricia E, O’Donnell-Luria, Anne, Valivullah, Zaheer, Lovgren, Alysia Kern, England, Elaina M, Agolini, Emanuele, Madden, Jill A, Schmitz-Abe, Klaus, Kritzer, Amy, Hawley, Pamela, Novelli, Antonio, Alfieri, Paolo, Colafati, Giovanna Stefania, Wieczorek, Dagmar, Platzer, Konrad, Luppe, Johannes, Koch-Hogrebe, Margarete, Jamra, Rami Abou, Neira-Fresneda, Juanita, Lehman, Anna, Boerkoel, Cornelius F, Seath, Kimberly, Clarke, Lorne, Study, CAUSES, van Ierland, Yvette, Argilli, Emanuela, Sherr, Elliott H, Maiorana, Andrea, Diel, Thilo, Hempel, Maja, Bierhals, Tatjana, Estévez, Raúl, Jentsch, Thomas J, Pusch, Michael, and Agrawal, Pankaj B

Subjects
Biological Sciences, Medical Physiology, Biomedical and Clinical Sciences, Genetics, Pediatric, Mental Health, Intellectual and Developmental Disabilities (IDD), Neurosciences, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adolescent, Animals, Child, Child, Preschool, Chloride Channels, Disease Models, Animal, Female, Homozygote, Humans, Infant, Infant, Newborn, Ion Channels, Male, Mice, Mice, Knockout, Mutation, Neurodevelopmental Disorders, Phenotype, CAUSES Study, CLCN, acidification, gain of function, hippocampus, intellectual disability, neurodevelopmental delay, pH sensitivity, voltage gated chloride channel, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

Published
2021

9. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Author

Rots, Dmitrijs, Chater-Diehl, Eric, Dingemans, Alexander JM, Goodman, Sarah J, Siu, Michelle T, Cytrynbaum, Cheryl, Choufani, Sanaa, Hoang, Ny, Walker, Susan, Awamleh, Zain, Charkow, Joshua, Meyn, Stephen, Pfundt, Rolph, Rinne, Tuula, Gardeitchik, Thatjana, de Vries, Bert BA, Deden, A Chantal, Leenders, Erika, Kwint, Michael, Stumpel, Constance TRM, Stevens, Servi JC, Vermeulen, Jeroen R, van Harssel, Jeske VT, Bosch, Danielle GM, van Gassen, Koen LI, van Binsbergen, Ellen, de Geus, Christa M, Brackel, Hein, Hempel, Maja, Lessel, Davor, Denecke, Jonas, Slavotinek, Anne, Strober, Jonathan, Crunk, Amy, Folk, Leandra, Wentzensen, Ingrid M, Yang, Hui, Zou, Fanggeng, Millan, Francisca, Person, Richard, Xie, Yili, Liu, Shuxi, Ousager, Lilian B, Larsen, Martin, Schultz-Rogers, Laura, Morava, Eva, Klee, Eric W, Berry, Ian R, Campbell, Jennifer, Lindstrom, Kristin, Pruniski, Brianna, Neumeyer, Ann M, Radley, Jessica A, Phornphutkul, Chanika, Schmidt, Berkley, Wilson, William G, Õunap, Katrin, Reinson, Karit, Pajusalu, Sander, van Haeringen, Arie, Ruivenkamp, Claudia, Cuperus, Roos, Santos-Simarro, Fernando, Palomares-Bralo, María, Pacio-Míguez, Marta, Ritter, Alyssa, Bhoj, Elizabeth, Tønne, Elin, Tveten, Kristian, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Rowe, Leah, Bunn, Jason, Saenz, Margarita, Platzer, Konrad, Mertens, Mareike, Caluseriu, Oana, Nowaczyk, Małgorzata JM, Cohn, Ronald D, Kannu, Peter, Alkhunaizi, Ebba, Chitayat, David, Scherer, Stephen W, Brunner, Han G, Vissers, Lisenka ELM, Kleefstra, Tjitske, Koolen, David A, and Weksberg, Rosanna

Subjects
Genetics, Clinical Research, Brain Disorders, Mental Health, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Abnormalities, Multiple, Adenosine Triphosphatases, Case-Control Studies, Cohort Studies, Craniofacial Abnormalities, DNA Methylation, Epigenesis, Genetic, Female, Genetic Predisposition to Disease, Growth Disorders, Heart Septal Defects, Ventricular, Humans, Infant, Newborn, Male, Mutation, Neurodevelopmental Disorders, Phenotype, DNA methylation signature, Floating-Harbor syndrome, SRCAP, epigenomics, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorders, non-FLHS SRCAP-related NDD, nonsense-mediated decay, speech delay, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Published
2021

11. AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia

Author

Terhal, Paulien, Venhuizen, Anton J., Lessel, Davor, Tan, Wen-Hann, Alswaid, Abdulrahman, Grün, Regina, Alzaidan, Hamad I., von Kroge, Simon, Ragab, Nada, Hempel, Maja, Kubisch, Christian, Novais, Eduardo, Cristobal, Alba, Tripolszki, Kornelia, Bauer, Peter, Fischer-Zirnsak, Björn, Nievelstein, Rutger A.J., van Dijk, Atty, Nikkels, Peter, Oheim, Ralf, Hahn, Heidi, Bertoli-Avella, Aida, Maurice, Madelon M., and Kornak, Uwe

Published
2023
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12. 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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13. De novo PHF5A variants are associated with craniofacial abnormalities, developmental delay, and hypospadias

Author

Harms, Frederike L., Dingemans, Alexander J.M., Hempel, Maja, Pfundt, Rolph, Bierhals, Tatjana, Casar, Christian, Müller, Christian, Niermeijer, Jikke-Mien F., Fischer, Jan, Jahn, Arne, Hübner, Christoph, Majore, Silvia, Agolini, Emanuele, Novelli, Antonio, van der Smagt, Jasper, Ernst, Robert, van Binsbergen, Ellen, Mancini, Grazia M.S., van Slegtenhorst, Marjon, Barakat, Tahsin S., Wakeling, Emma L., Kamath, Arveen, Downie, Lilian, Pais, Lynn, White, Susan M., de Vries, Bert B.A., and Kutsche, Kerstin

Published
2023
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14. European Autism GEnomics Registry (EAGER): protocol for a multicentre cohort study and registry

Author

Bloomfield, Madeleine, primary, Lautarescu, Alexandra, additional, Heraty, Síofra, additional, Douglas, Sarah, additional, Violland, Pierre, additional, Plas, Roderik, additional, Ghosh, Anjuli, additional, Van den Bosch, Katrien, additional, Eaton, Eliza, additional, Absoud, Michael, additional, Battini, Roberta, additional, Blázquez Hinojosa, Ana, additional, Bolshakova, Nadia, additional, Bölte, Sven, additional, Bonanni, Paolo, additional, Borg, Jacqueline, additional, Calderoni, Sara, additional, Calvo Escalona, Rosa, additional, Castelo-Branco, Miguel, additional, Castro-Fornieles, Josefina, additional, Caro, Pilar, additional, Cliquet, Freddy, additional, Danieli, Alberto, additional, Delorme, Richard, additional, Elia, Maurizio, additional, Hempel, Maja, additional, Leblond, Claire S, additional, Madeira, Nuno, additional, McAlonan, Grainne, additional, Milone, Roberta, additional, Molloy, Ciara J, additional, Mouga, Susana, additional, Montiel, Virginia, additional, Pina Rodrigues, Ana, additional, Schaaf, Christian P, additional, Serrano, Mercedes, additional, Tammimies, Kristiina, additional, Tye, Charlotte, additional, Vigevano, Federico, additional, Oliveira, Guiomar, additional, Mazzone, Beatrice, additional, O’Neill, Cara, additional, Pender, Julie, additional, Romero, Verena, additional, Tillmann, Julian, additional, Oakley, Bethany, additional, Murphy, Declan G M, additional, Gallagher, Louise, additional, Bourgeron, Thomas, additional, Chatham, Christopher, additional, and Charman, Tony, additional

Published
2024
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15. KAT6A Syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants

Author

Kennedy, Joanna, Goudie, David, Blair, Edward, Chandler, Kate, Joss, Shelagh, McKay, Victoria, Green, Andrew, Armstrong, Ruth, Lees, Melissa, Kamien, Benjamin, Hopper, Bruce, Tan, Tiong Yang, Yap, Patrick, Stark, Zornitza, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Macnamara, Ellen, Murphy, Jennifer L, McCormick, Elizabeth, Hakonarson, Hakon, Falk, Marni J, Li, Dong, Blackburn, Patrick, Klee, Eric, Babovic-Vuksanovic, Dusica, Schelley, Susan, Hudgins, Louanne, Kant, Sarina, Isidor, Bertrand, Cogne, Benjamin, Bradbury, Kimberley, Williams, Mark, Patel, Chirag, Heussler, Helen, Duff-Farrier, Celia, Lakeman, Phillis, Scurr, Ingrid, Kini, Usha, Elting, Mariet, Reijnders, Margot, Schuurs-Hoeijmakers, Janneke, Wafik, Mohamed, Blomhoff, Anne, Ruivenkamp, Claudia AL, Nibbeling, Esther, Dingemans, Alexander JM, Douine, Emilie D, Nelson, Stanley F, Hempel, Maja, Bierhals, Tatjana, Lessel, Davor, Johannsen, Jessika, Arboleda, Valerie A, and Newbury-Ecob, Ruth

Subjects
Biological Sciences, Genetics, Prevention, Brain Disorders, Rare Diseases, Pediatric, Clinical Research, Digestive Diseases, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Developmental Disabilities, Exome, Female, Genetic Association Studies, Genotype, Histone Acetyltransferases, Humans, Infant, Intellectual Disability, Male, Microcephaly, Mutation, Phenotype, Protein Isoforms, Young Adult, genetic diagnosis, phenotypic spectrum, KAT6A syndrome, chromatin modifiers, intellectual disability, DDD Study, KAT6A syndrome, chromatin modifiers, intellectual disability, Clinical Sciences, Genetics & Heredity
Abstract

PurposePathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported.MethodsWe obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review.ResultsWe identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction.ConclusionOur data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

Published
2019

18. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A., Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H., Alston, Charlotte L., Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes, Hayflick, Susan J., Hempel, Maja, Itkis, Yulia S., Kishita, Yoshihito, Klopstock, Thomas, Krylova, Tatiana D., Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F., Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, Schwarzmayr, Thomas, Smet, Joél, Staufner, Christian, Stenton, Sarah L., Strom, Tim M., Terrile, Caterina, Tort, Frederic, Van Coster, Rudy, Vanlander, Arnaud, Wagner, Matias, Xu, Manting, Fang, Fang, Ghezzi, Daniele, Mayr, Johannes A., Piekutowska-Abramczuk, Dorota, Ribes, Antonia, Rötig, Agnès, Taylor, Robert W., Wortmann, Saskia B., Murayama, Kei, Meitinger, Thomas, Gagneur, Julien, and Prokisch, Holger

Published
2022
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19. Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males

Author

Kreienkamp, Hans-Jürgen, Wagner, Matias, Weigand, Heike, McConkie-Rossell, Allyn, McDonald, Marie, Keren, Boris, Mignot, Cyril, Gauthier, Julie, Soucy, Jean-François, Michaud, Jacques L., Dumas, Meghan, Smith, Rosemarie, Löbel, Ulrike, Hempel, Maja, Kubisch, Christian, Denecke, Jonas, Campeau, Philippe M., Bain, Jennifer M., and Lessel, Davor

Published
2022
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22. Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes

Author

Martin-Almedina, Silvia, Ogmen, Kazim, Sackey, Ege, Grigoriadis, Dionysios, Karapouliou, Christina, Nadarajah, Noeline, Ebbing, Cathrine, Lord, Jenny, Mellis, Rhiannon, Kortuem, Fanny, Dinulos, Mary Beth, Polun, Cassandra, Bale, Sherri, Atton, Giles, Robinson, Alexandra, Reigstad, Hallvard, Houge, Gunnar, von der Wense, Axel, Becker, Wolf-Henning, Jeffery, Steve, Mortimer, Peter S., Gordon, Kristiana, Josephs, Katherine S., Robart, Sarah, Kilby, Mark D., Vallee, Stephanie, Gorski, Jerome L., Hempel, Maja, Berland, Siren, Mansour, Sahar, and Ostergaard, Pia

Published
2021
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23. Genetic landscape of pediatric acute liver failure of indeterminate origin

Author

MDL patientenzorg, Lenz, Dominic, Schlieben, Lea D, Shimura, Masaru, Bianzano, Alyssa, Smirnov, Dmitrii, Kopajtich, Robert, Berutti, Riccardo, Adam, Rüdiger, Aldrian, Denise, Baric, Ivo, Baumann, Ulrich, Bozbulut, Neslihan Eksi, Brugger, Melanie, Brunet, Theresa, Bufler, Philip, Burnytė, Birutė, Calvo, Pier Luigi, Crushell, Ellen, Dalgıç, Buket, Das, Anibh M, Dezsőfi, Antal, Distelmaier, Felix, Fichtner, Alexander, Freisinger, Peter, Garbade, Sven F, Gaspar, Harald, Goujon, Louise, Hadzic, Nedim, Hartleif, Steffen, Hegen, Bianca, Hempel, Maja, Henning, Stephan, Hoerning, Andre, Houwen, Roderick, Hughes, Joanne, Iorio, Raffaele, Iwanicka-Pronicka, Katarzyna, Jankofsky, Martin, Junge, Norman, Kanavaki, Ino, Kansu, Aydan, Kaspar, Sonja, Kathemann, Simone, Kelly, Deidre, Kırsaçlıoğlu, Ceyda Tuna, Knoppke, Birgit, Kohl, Martina, Kölbel, Heike, Kölker, Stefan, Konstantopoulou, Vassiliki, Krylova, Tatiana, Kuloğlu, Zarife, Kuster, Alice, Laass, Martin W, Lainka, Elke, Lurz, Eberhard, Mandel, Hanna, Mayerhanser, Katharina, Mayr, Johannes A, McKiernan, Patrick, McLean, Patricia, McLin, Valerie, Mention, Karine, Müller, Hanna, Pasquier, Laurent, Pavlov, Martin, Pechatnikova, Natalia, Peters, Bianca, Petković Ramadža, Danijela, Piekutowska-Abramczuk, Dorota, Pilic, Denisa, Rajwal, Sanjay, Rock, Nathalie, Roetig, Agnès, Santer, René, Schenk, Wilfried, Semenova, Natalia, Sokollik, Christiane, Sturm, Ekkehard, Taylor, Robert W, Tschiedel, Eva, Urbonas, Vaidotas, Urreizti, Roser, Vermehren, Jan, Vockley, Jerry, Vogel, Georg-Friedrich, Wagner, Matias, van der Woerd, Wendy, Wortmann, Saskia B, Zakharova, Ekaterina, Hoffmann, Georg Friedrich, Meitinger, Thomas, Murayama, Kei, Staufner, Christian, Prokisch, Holger, MDL patientenzorg, Lenz, Dominic, Schlieben, Lea D, Shimura, Masaru, Bianzano, Alyssa, Smirnov, Dmitrii, Kopajtich, Robert, Berutti, Riccardo, Adam, Rüdiger, Aldrian, Denise, Baric, Ivo, Baumann, Ulrich, Bozbulut, Neslihan Eksi, Brugger, Melanie, Brunet, Theresa, Bufler, Philip, Burnytė, Birutė, Calvo, Pier Luigi, Crushell, Ellen, Dalgıç, Buket, Das, Anibh M, Dezsőfi, Antal, Distelmaier, Felix, Fichtner, Alexander, Freisinger, Peter, Garbade, Sven F, Gaspar, Harald, Goujon, Louise, Hadzic, Nedim, Hartleif, Steffen, Hegen, Bianca, Hempel, Maja, Henning, Stephan, Hoerning, Andre, Houwen, Roderick, Hughes, Joanne, Iorio, Raffaele, Iwanicka-Pronicka, Katarzyna, Jankofsky, Martin, Junge, Norman, Kanavaki, Ino, Kansu, Aydan, Kaspar, Sonja, Kathemann, Simone, Kelly, Deidre, Kırsaçlıoğlu, Ceyda Tuna, Knoppke, Birgit, Kohl, Martina, Kölbel, Heike, Kölker, Stefan, Konstantopoulou, Vassiliki, Krylova, Tatiana, Kuloğlu, Zarife, Kuster, Alice, Laass, Martin W, Lainka, Elke, Lurz, Eberhard, Mandel, Hanna, Mayerhanser, Katharina, Mayr, Johannes A, McKiernan, Patrick, McLean, Patricia, McLin, Valerie, Mention, Karine, Müller, Hanna, Pasquier, Laurent, Pavlov, Martin, Pechatnikova, Natalia, Peters, Bianca, Petković Ramadža, Danijela, Piekutowska-Abramczuk, Dorota, Pilic, Denisa, Rajwal, Sanjay, Rock, Nathalie, Roetig, Agnès, Santer, René, Schenk, Wilfried, Semenova, Natalia, Sokollik, Christiane, Sturm, Ekkehard, Taylor, Robert W, Tschiedel, Eva, Urbonas, Vaidotas, Urreizti, Roser, Vermehren, Jan, Vockley, Jerry, Vogel, Georg-Friedrich, Wagner, Matias, van der Woerd, Wendy, Wortmann, Saskia B, Zakharova, Ekaterina, Hoffmann, Georg Friedrich, Meitinger, Thomas, Murayama, Kei, Staufner, Christian, and Prokisch, Holger

Published
2024

24. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Author

Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Kaiyrzhanov, Rauan, Rad, Aboulfazl, Lin, Sheng-Jia, Bertoli-Avella, Aida, Kallemeijn, Wouter W, Godwin, Annie, Zaki, Maha S, Huang, Kevin, Lau, Tracy, Petree, Cassidy, Efthymiou, Stephanie, Ghayoor Karimiani, Ehsan, Hempel, Maja, Normand, Elizabeth A, Rudnik-Schöneborn, Sabine, Schatz, Ulrich A, Baggelaar, Marc P, Ilyas, Muhammad, Sultan, Tipu, Alvi, Javeria Raza, Ganieva, Manizha, Fowler, Ben, Aanicai, Ruxandra, Akay Tayfun, Gulsen, Al Saman, Abdulaziz, Alswaid, Abdulrahman, Amiri, Nafise, Asilova, Nilufar, Shotelersuk, Vorasuk, Yeetong, Patra, Azam, Matloob, Babaei, Meisam, Bahrami Monajemi, Gholamreza, Mohammadi, Pouria, Samie, Saeed, Banu, Selina Husna, Basto, Jorge Pinto, Kortüm, Fanny, Bauer, Mislen, Bauer, Peter, Beetz, Christian, Garshasbi, Masoud, Hameed Issa, Awatif, Eyaid, Wafaa, Ahmed, Hind, Hashemi, Narges, Hassanpour, Kazem, Herman, Isabella, Ibrohimov, Sherozjon, Abdul-Majeed, Ban A, Imdad, Maria, Isrofilov, Maksudjon, Kaiyal, Qassem, Khan, Suliman, Kirmse, Brian, Koster, Janet, Lourenço, Charles Marques, Mitani, Tadahiro, Moldovan, Oana, Murphy, David, Najafi, Maryam, Pehlivan, Davut, Rocha, Maria Eugenia, Salpietro, Vincenzo, Schmidts, Miriam, Shalata, Adel, Mahroum, Mohammad, Talbeya, Jawabreh Kassem, Taylor, Robert W, Vazquez, Dayana, Vetro, Annalisa, Waterham, Hans R, Zaman, Mashaya, Schrader, Tina A, Chung, Wendy K, Guerrini, Renzo, Lupski, James R, Gleeson, Joseph, Suri, Mohnish, Jamshidi, Yalda, Bhatia, Kailash P, Vona, Barbara, Schrader, Michael, Severino, Mariasavina, Guille, Matthew, Tate, Edward W, Varshney, Gaurav K, Houlden, Henry, Maroofian, Reza, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Kaiyrzhanov, Rauan, Rad, Aboulfazl, Lin, Sheng-Jia, Bertoli-Avella, Aida, Kallemeijn, Wouter W, Godwin, Annie, Zaki, Maha S, Huang, Kevin, Lau, Tracy, Petree, Cassidy, Efthymiou, Stephanie, Ghayoor Karimiani, Ehsan, Hempel, Maja, Normand, Elizabeth A, Rudnik-Schöneborn, Sabine, Schatz, Ulrich A, Baggelaar, Marc P, Ilyas, Muhammad, Sultan, Tipu, Alvi, Javeria Raza, Ganieva, Manizha, Fowler, Ben, Aanicai, Ruxandra, Akay Tayfun, Gulsen, Al Saman, Abdulaziz, Alswaid, Abdulrahman, Amiri, Nafise, Asilova, Nilufar, Shotelersuk, Vorasuk, Yeetong, Patra, Azam, Matloob, Babaei, Meisam, Bahrami Monajemi, Gholamreza, Mohammadi, Pouria, Samie, Saeed, Banu, Selina Husna, Basto, Jorge Pinto, Kortüm, Fanny, Bauer, Mislen, Bauer, Peter, Beetz, Christian, Garshasbi, Masoud, Hameed Issa, Awatif, Eyaid, Wafaa, Ahmed, Hind, Hashemi, Narges, Hassanpour, Kazem, Herman, Isabella, Ibrohimov, Sherozjon, Abdul-Majeed, Ban A, Imdad, Maria, Isrofilov, Maksudjon, Kaiyal, Qassem, Khan, Suliman, Kirmse, Brian, Koster, Janet, Lourenço, Charles Marques, Mitani, Tadahiro, Moldovan, Oana, Murphy, David, Najafi, Maryam, Pehlivan, Davut, Rocha, Maria Eugenia, Salpietro, Vincenzo, Schmidts, Miriam, Shalata, Adel, Mahroum, Mohammad, Talbeya, Jawabreh Kassem, Taylor, Robert W, Vazquez, Dayana, Vetro, Annalisa, Waterham, Hans R, Zaman, Mashaya, Schrader, Tina A, Chung, Wendy K, Guerrini, Renzo, Lupski, James R, Gleeson, Joseph, Suri, Mohnish, Jamshidi, Yalda, Bhatia, Kailash P, Vona, Barbara, Schrader, Michael, Severino, Mariasavina, Guille, Matthew, Tate, Edward W, Varshney, Gaurav K, Houlden, Henry, and Maroofian, Reza

Published
2024

25. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

Author

Begemann, Anaïs, Sticht, Heinrich, Begtrup, Amber, Vitobello, Antonio, Faivre, Laurence, Banka, Siddharth, Alhaddad, Bader, Asadollahi, Reza, Becker, Jessica, Bierhals, Tatjana, Brown, Kathleen E., Bruel, Ange-Line, Brunet, Theresa, Carneiro, Maryline, Cremer, Kirsten, Day, Robert, Denommé-Pichon, Anne-Sophie, Dyment, Dave A., Engels, Hartmut, Fisher, Rachel, Goh, Elaine S., Hajianpour, M. J., Haertel, Lucia Ribeiro Machado, Hauer, Nadine, Hempel, Maja, Herget, Theresia, Johannsen, Jessika, Kraus, Cornelia, Le Guyader, Gwenaël, Lesca, Gaetan, Mau-Them, Frédéric Tran, McDermott, John Henry, McWalter, Kirsty, Meyer, Pierre, Õunap, Katrin, Popp, Bernt, Reimand, Tiia, Riedhammer, Korbinian M., Russo, Martina, Sadleir, Lynette G., Saenz, Margarita, Schiff, Manuel, Schuler, Elisabeth, Syrbe, Steffen, Van der Ven, Amelie Theresa, Verloes, Alain, Willems, Marjolaine, Zweier, Christiane, Steindl, Katharina, Zweier, Markus, and Rauch, Anita

Published
2021
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27. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author

Kim, Jung-Hyun, Shinde, Deepali N, Reijnders, Margot RF, Hauser, Natalie S, Belmonte, Rebecca L, Wilson, Gregory R, Bosch, Daniëlle GM, Bubulya, Paula A, Shashi, Vandana, Petrovski, Slavé, Stone, Joshua K, Park, Eun Young, Veltman, Joris A, Sinnema, Margje, Stumpel, Connie TRM, Draaisma, Jos M, Nicolai, Joost, Genomics, University of Washington Center for Mendelian, Yntema, Helger G, Lindstrom, Kristin, de Vries, Bert BA, Jewett, Tamison, Santoro, Stephanie L, Vogt, Julie, Study, Deciphering Developmental Disorders, Bachman, Kristine K, Seeley, Andrea H, Krokosky, Alyson, Turner, Clesson, Rohena, Luis, Hempel, Maja, Kortüm, Fanny, Lessel, Davor, Neu, Axel, Strom, Tim M, Wieczorek, Dagmar, Bramswig, Nuria, Laccone, Franco A, Behunova, Jana, Rehder, Helga, Gordon, Christopher T, Rio, Marlène, Romana, Serge, Tang, Sha, El-Khechen, Dima, Cho, Megan T, McWalter, Kirsty, Douglas, Ganka, Baskin, Berivan, Begtrup, Amber, Funari, Tara, Schoch, Kelly, Stegmann, Alexander PA, Stevens, Servi JC, Zhang, Dong-Er, Traver, David, Yao, Xu, MacArthur, Daniel G, Brunner, Han G, Mancini, Grazia M, Myers, Richard M, Owen, Laurie B, Lim, Ssang-Taek, Stachura, David L, Vissers, Lisenka ELM, and Ahn, Eun-Young Erin

Subjects
Brain Disorders, Congenital Structural Anomalies, Neurosciences, Mental Health, Clinical Research, Genetics, Pediatric, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Congenital, Animals, Brain, DNA-Binding Proteins, Developmental Disabilities, Eye Abnormalities, Female, Genes, Essential, Haploinsufficiency, Head, Heterozygote, Humans, Intellectual Disability, Male, Metabolic Diseases, Minor Histocompatibility Antigens, Mutation, Pedigree, RNA Splicing, RNA, Messenger, Spine, Syndrome, Zebrafish, University of Washington Center for Mendelian Genomics, Deciphering Developmental Disorders Study, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

Published
2016

29. Novel pericentric inversion inv(9)(p23q22.3) in unrelated individuals with fertility problems in the Southeast European population

Author

Sismani, Carolina, Rapti, Stamatia-Maria, Iliopoulou, Pavlina, Spring, Anastasia, Neroutsou, Rozalia, Lagou, Magdalini, Robola, Marianna, Tsitsopoulos, Efstathios, Kousoulidou, Ludmila, Alexandrou, Angelos, Papaevripidou, Ioannis, Theodosiou, Athina, Syrrou, Maria, Fuchs, Sigrid, Hempel, Maja, Huhle, Dagmar, Liehr, Thomas, Ziegler, Monika, Duesberg, Max, and Velissariou, Voula

Published
2020
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30. Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus

Author

Wagner, Matias, Lévy, Jonathan, Jung-Klawitter, Sabine, Bakhtiari, Somayeh, Monteiro, Fabiola, Maroofian, Reza, Bierhals, Tatjana, Hempel, Maja, Elmaleh-Bergès, Monique, Kitajima, Joao P., Kim, Chong A., Salomao, Julia G., Amor, David J., Cooper, Monica S., Perrin, Laurence, Pipiras, Eva, Neu, Axel, Doosti, Mohammad, Karimiani, Ehsan G., Toosi, Mehran B., Houlden, Henry, Jin, Sheng Chih, Si, Yue C., Rodan, Lance H., Venselaar, Hanka, Kruer, Michael C., Kok, Fernando, Hoffmann, Georg F., Strom, Tim M., Wortmann, Saskia B., Tabet, Anne-Claude, and Opladen, Thomas

Published
2020
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32. Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients

Author

Staufner, Christian, Peters, Bianca, Wagner, Matias, Alameer, Seham, Barić, Ivo, Broué, Pierre, Bulut, Derya, Church, Joseph A., Crushell, Ellen, Dalgıç, Buket, Das, Anibh M., Dick, Anke, Dikow, Nicola, Dionisi-Vici, Carlo, Distelmaier, Felix, Bozbulut, Neslihan Ekşi, Feillet, François, Gonzales, Emmanuel, Hadzic, Nedim, Hauck, Fabian, Hegarty, Robert, Hempel, Maja, Herget, Theresia, Klein, Christoph, Konstantopoulou, Vassiliki, Kopajtich, Robert, Kuster, Alice, Laass, Martin W., Lainka, Elke, Larson-Nath, Catherine, Leibner, Alexander, Lurz, Eberhard, Mayr, Johannes A., McKiernan, Patrick, Mention, Karine, Moog, Ute, Mungan, Neslihan Onenli, Riedhammer, Korbinian M., Santer, René, Palafoll, Irene Valenzuela, Vockley, Jerry, Westphal, Dominik S., Wiedemann, Arnaud, Wortmann, Saskia B., Diwan, Gaurav D., Russell, Robert B., Prokisch, Holger, Garbade, Sven F., Kölker, Stefan, Hoffmann, Georg F., and Lenz, Dominic

Published
2020
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33. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

Author

Kaiyrzhanov, Rauan, Rad, Aboulfazl, Lin, Sheng-Jia, Bertoli-Avella, Aida, Kallemeijn, Wouter W, Godwin, Annie, Zaki, Maha S, Huang, Kevin, Lau, Tracy, Petree, Cassidy, Efthymiou, Stephanie, Karimiani, Ehsan Ghayoor, Hempel, Maja, Normand, Elizabeth A, Rudnik-Schöneborn, Sabine, Schatz, Ulrich A, Baggelaar, Marc P, Ilyas, Muhammad, Sultan, Tipu, and Alvi, Javeria Raza

Subjects
MOVEMENT disorders, AGENESIS of corpus callosum, NEUROLOGICAL disorders, SYNDROMES, FACIAL abnormalities, CEREBELLAR ataxia, CHEMICAL models
Abstract

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N -myristoylation of proteins via N -myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N -myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1–50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6 -deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N -myristoylated proteins in patient-derived fibroblasts. N -myristoylation was similarly affected in acbd6 -deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Genetic landscape of pediatric acute liver failure of indeterminate origin

Author

Lenz, Dominic, primary, Schlieben, Lea D., additional, Shimura, Masaru, additional, Bianzano, Alyssa, additional, Smirnov, Dmitrii, additional, Kopajtich, Robert, additional, Berutti, Riccardo, additional, Adam, Rüdiger, additional, Aldrian, Denise, additional, Baric, Ivo, additional, Baumann, Ulrich, additional, Bozbulut, Neslihan E., additional, Brugger, Melanie, additional, Brunet, Theresa, additional, Bufler, Philip, additional, Burnytė, Birutė, additional, Calvo, Pier L., additional, Crushell, Ellen, additional, Dalgiç, Buket, additional, Das, Anibh M., additional, Dezsőfi, Antal, additional, Distelmaier, Felix, additional, Fichtner, Alexander, additional, Freisinger, Peter, additional, Garbade, Sven F., additional, Gaspar, Harald, additional, Goujon, Louise, additional, Hadzic, Nedim, additional, Hartleif, Steffen, additional, Hegen, Bianca, additional, Hempel, Maja, additional, Henning, Stephan, additional, Hoerning, Andre, additional, Houwen, Roderick, additional, Hughes, Joanne, additional, Iorio, Raffaele, additional, Iwanicka-Pronicka, Katarzyna, additional, Jankofsky, Martin, additional, Junge, Norman, additional, Kanavaki, Ino, additional, Kansu, Aydan, additional, Kaspar, Sonja, additional, Kathemann, Simone, additional, Kelly, Deidre, additional, Kirsaçlioğlu, Ceyda T., additional, Knoppke, Birgit, additional, Kohl, Martina, additional, Kölbel, Heike, additional, Kölker, Stefan, additional, Konstantopoulou, Vassiliki, additional, Krylova, Tatiana, additional, Kuloğlu, Zarife, additional, Kuster, Alice, additional, Laass, Martin W., additional, Lainka, Elke, additional, Lurz, Eberhard, additional, Mandel, Hanna, additional, Mayerhanser, Katharina, additional, Mayr, Johannes A., additional, McKiernan, Patrick, additional, McClean, Patricia, additional, McLin, Valerie, additional, Mention, Karine, additional, Müller, Hanna, additional, Pasquier, Laurent, additional, Pavlov, Martin, additional, Pechatnikova, Natalia, additional, Peters, Bianca, additional, Petković Ramadža, Danijela, additional, Piekutowska-Abramczuk, Dorota, additional, Pilic, Denisa, additional, Rajwal, Sanjay, additional, Rock, Nathalie, additional, Roetig, Agnès, additional, Santer, René, additional, Schenk, Wilfried, additional, Semenova, Natalia, additional, Sokollik, Christiane, additional, Sturm, Ekkehard, additional, Taylor, Robert W., additional, Tschiedel, Eva, additional, Urbonas, Vaidotas, additional, Urreizti, Roser, additional, Vermehren, Jan, additional, Vockley, Jerry, additional, Vogel, Georg-Friedrich, additional, Wagner, Matias, additional, van der Woerd, Wendy, additional, Wortmann, Saskia B., additional, Zakharova, Ekaterina, additional, Hoffmann, Georg F., additional, Meitinger, Thomas, additional, Murayama, Kei, additional, Staufner, Christian, additional, and Prokisch, Holger, additional

Published
2023
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35. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Author

Kaiyrzhanov, Rauan, primary, Rad, Aboulfazl, additional, Lin, Sheng-Jia, additional, Bertoli-Avella, Aida, additional, Kallemeijn, Wouter W, additional, Godwin, Annie, additional, Zaki, Maha S, additional, Huang, Kevin, additional, Lau, Tracy, additional, Petree, Cassidy, additional, Efthymiou, Stephanie, additional, Ghayoor Karimiani, Ehsan, additional, Hempel, Maja, additional, Normand, Elizabeth A, additional, Rudnik-Schöneborn, Sabine, additional, Schatz, Ulrich A, additional, Baggelaar, Marc P, additional, Ilyas, Muhammad, additional, Sultan, Tipu, additional, Alvi, Javeria Raza, additional, Ganieva, Manizha, additional, Fowler, Ben, additional, Aanicai, Ruxandra, additional, Akay Tayfun, Gulsen, additional, Al Saman, Abdulaziz, additional, Alswaid, Abdulrahman, additional, Amiri, Nafise, additional, Asilova, Nilufar, additional, Shotelersuk, Vorasuk, additional, Yeetong, Patra, additional, Azam, Matloob, additional, Babaei, Meisam, additional, Bahrami Monajemi, Gholamreza, additional, Mohammadi, Pouria, additional, Samie, Saeed, additional, Banu, Selina Husna, additional, Basto, Jorge Pinto, additional, Kortüm, Fanny, additional, Bauer, Mislen, additional, Bauer, Peter, additional, Beetz, Christian, additional, Garshasbi, Masoud, additional, Hameed Issa, Awatif, additional, Eyaid, Wafaa, additional, Ahmed, Hind, additional, Hashemi, Narges, additional, Hassanpour, Kazem, additional, Herman, Isabella, additional, Ibrohimov, Sherozjon, additional, Abdul-Majeed, Ban A, additional, Imdad, Maria, additional, Isrofilov, Maksudjon, additional, Kaiyal, Qassem, additional, Khan, Suliman, additional, Kirmse, Brian, additional, Koster, Janet, additional, Lourenço, Charles Marques, additional, Mitani, Tadahiro, additional, Moldovan, Oana, additional, Murphy, David, additional, Najafi, Maryam, additional, Pehlivan, Davut, additional, Rocha, Maria Eugenia, additional, Salpietro, Vincenzo, additional, Schmidts, Miriam, additional, Shalata, Adel, additional, Mahroum, Mohammad, additional, Talbeya, Jawabreh Kassem, additional, Taylor, Robert W, additional, Vazquez, Dayana, additional, Vetro, Annalisa, additional, Waterham, Hans R, additional, Zaman, Mashaya, additional, Schrader, Tina A, additional, Chung, Wendy K, additional, Guerrini, Renzo, additional, Lupski, James R, additional, Gleeson, Joseph, additional, Suri, Mohnish, additional, Jamshidi, Yalda, additional, Bhatia, Kailash P, additional, Vona, Barbara, additional, Schrader, Michael, additional, Severino, Mariasavina, additional, Guille, Matthew, additional, Tate, Edward W, additional, Varshney, Gaurav K, additional, Houlden, Henry, additional, and Maroofian, Reza, additional

Published
2023
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36. European Autism GEnomics Registry (EAGER): Protocol for a multicentre cohort study and registry

Author

Bloomfield, Madeleine, primary, Lautarescu, Alexandra, additional, Heraty, Siofra, additional, Douglas, Sarah, additional, Violland, Pierre, additional, Plas, Roderik, additional, Ghosh, Anjuli, additional, Van den Bosch, Katrien, additional, Eaton, Eliza, additional, Absoud, Michael, additional, Battini, Roberta, additional, Blazquez Hinojosa, Ana, additional, Bolshakova, Nadia, additional, Bolte, Sven, additional, Bonanni, Paolo, additional, Borg, Jacqueline, additional, Calderoni, Sara, additional, Calvo Escalona, Rosa, additional, Castelo-Branco, Miguel, additional, Castro-Fornieles, Josefina, additional, Caro, Pilar, additional, Danieli, Alberto, additional, Delorme, Richard, additional, Elia, Maurizio, additional, Hempel, Maja, additional, Madeira, Nuno, additional, McAlonan, Grainne, additional, Milone, Roberta, additional, Molloy, Ciara J, additional, Mouga, Susana, additional, Montiel, Virginia, additional, Pina Rodrigues, Ana, additional, Schaaf, Christian P, additional, Serrano, Mercedes, additional, Tammimies, Kristiina, additional, Tye, Charlotte, additional, Vigevano, Federico, additional, Oliveira, Guiomar, additional, Mazzone, Beatrice, additional, O'Neill, Cara, additional, Romero, Verena, additional, Tillmann, Julian, additional, Oakley, Bethany, additional, Murphy, Declan, additional, Gallagher, Louise, additional, Bourgeron, Thomas, additional, Chatham, Christopher, additional, and Charman, Tony, additional

Published
2023
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37. Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis

Author

Burkhalter, Martin D., Sridhar, Arthi, Sampaio, Pedro, Jacinto, Raquel, Burczyk, Martina S., Donow, Cornelia, Investigators, Max AngenendCompetence Network for Congenital Heart Defects, Hempel, Maja, Walther, Paul, Pennekamp, Petra, Omran, Heymut, Lopes, Susana S., Ware, Stephanie M., and Philipp, Melanie

Subjects
Congenital heart defects -- Analysis, Heart diseases -- Analysis, Genes -- Analysis, Medical research -- Analysis, Genetic disorders -- Analysis, Mitochondrial DNA -- Analysis, Biosynthesis, Genomics, Newborn infants, Phenotypes, DNA, Genomes, Cardiovascular diseases, RNA, Health care industry
Abstract

About 1% of all newborns are affected by congenital heart disease (CHD). Recent findings identify aberrantly functioning cilia as a possible source for CHD. Faulty cilia also prevent the development of proper left-right asymmetry and cause heterotaxy, the incorrect placement of visceral organs. Intriguingly, signaling cascades such as mTOR that influence mitochondrial biogenesis also affect ciliogenesis, and can cause heterotaxy-like phenotypes in zebrafish. Here, we identify levels of mitochondrial function as a determinant for ciliogenesis and a cause for heterotaxy. We detected reduced mitochondrial DNA content in biopsies of heterotaxy patients. Manipulation of mitochondrial function revealed a reciprocal influence on ciliogenesis and affected cilia-dependent processes in zebrafish, human fibroblasts and Tetrahymena thermophila. Exome analysis of heterotaxy patients revealed an increased burden of rare damaging variants in mitochondria-associated genes as compared with 1000 Genome controls. Knock down of such candidate genes caused cilia elongation and ciliopathy-like phenotypes in zebrafish, which could not be rescued by RNA encoding damaging rare variants identified in heterotaxy patients. Our findings suggest that ciliogenesis is coupled to the abundance and function of mitochondria. Our data further reveal disturbed mitochondrial function as an underlying cause for heterotaxy- linked CHD and provide a mechanism for unexplained phenotypes of mitochondrial disease., Introduction Cilia are tubulin-based extensions, which can be motile or immotile. Immotile cilia, also known as primary cilia, exist as monocilia emanating from most vertebrate cells upon entry into G0 [...]

Published
2019
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38. Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy

Author

Johannesen, Katrine M., Mitter, Diana, Janowski, Robert, Roth, Christian, Toulouse, Joseph, Poulat, Anne-Lise, Ville, Dorothee M., Chatron, Nicolas, Brilstra, Eva, Geleijns, Karin, Born, Alfred Peter, McLean, Scott, Nugent, Kimberly, Baynam, Gareth, Poulton, Cathryn, Dreyer, Lauren, Gration, Dylan, Schulz, Solveig, Dieckmann, Andrea, Helbig, Katherine L., Merkenschlager, Andreas, Jamra, Rami, Finck, Anja, Gardella, Elena, Hjalgrim, Helle, Mirzaa, Ghayda, Brancati, Francesco, Bierhals, Tatjana, Denecke, Jonas, Hempel, Maja, Lemke, Johannes R., Rubboli, Guido, Muschke, Petra, Guerrini, Renzo, Vetro, Annalisa, Niessing, Dierk, Lesca, Gaetan, and Møller, Rikke S.

Published
2019
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39. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients

Author

Renner, Sina, Schüler, Helke, Alawi, Malik, Kolbe, Verena, Rybczynski, Meike, Woitschach, Rixa, Sheikhzadeh, Sara, Stark, Veronika C., Olfe, Jakob, Roser, Elke, Seggewies, Friederike Sophia, Mahlmann, Adrian, Hempel, Maja, Hartmann, Melanie J., Hillebrand, Mathias, Wieczorek, Dagmar, Volk, Alexander Erich, Kloth, Katja, Koch-Hogrebe, Margarete, Abou Jamra, Rami, Mitter, Diana, Altmüller, Janine, Wey-Fabrizius, Alexandra, Petersen, Christine, Rau, Isabella, Borck, Guntram, Kubisch, Christian, Mir, Thomas S., von Kodolitsch, Yskert, Kutsche, Kerstin, and Rosenberger, Georg

Published
2019
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40. Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability

Author

Verheije, Rosalind, Kupchik, Gabriel S., Isidor, Bertrand, Kroes, Hester Y., Lynch, Sally Ann, Hawkes, Lara, Hempel, Maja, Gelb, Bruce D., Ghoumid, Jamal, D’Amours, Guylaine, Chandler, Kate, Dubourg, Christèle, Loddo, Sara, Tümer, Zeynep, Shaw-Smith, Charles, Nizon, Mathilde, Shevell, Michael, Van Hoof, Evelien, Anyane-Yeboa, Kwame, Cerbone, Gaetana, Clayton-Smith, Jill, Cogné, Benjamin, Corre, Pierre, Corveleyn, Anniek, De Borre, Marie, Hjortshøj, Tina Duelund, Fradin, Mélanie, Gewillig, Marc, Goldmuntz, Elizabeth, Hens, Greet, Lemyre, Emmanuelle, Journel, Hubert, Kini, Usha, Kortüm, Fanny, Le Caignec, Cedric, Novelli, Antonio, Odent, Sylvie, Petit, Florence, Revah-Politi, Anya, Stong, Nicholas, Strom, Tim M., van Binsbergen, Ellen, DDD study, Devriendt, Koenraad, and Breckpot, Jeroen

Published
2019
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41. Biallelic loss-of-function variants of SLC12A9 cause lysosome dysfunction and a syndromic neurodevelopmental disorder

Author

Accogli, Andrea, Park, Young N., Lenk, Guy M., Severino, Mariasavina, Scala, Marcello, Denecke, Jonas, Hempel, Maja, Lessel, Davor, Kortüm, Fanny, Salpietro, Vincenzo, de Marco, Patrizia, Guerrisi, Sara, Torella, Annalaura, Nigro, Vincenzo, Srour, Myriam, Turro, Ernest, Labarque, Veerle, Freson, Kathleen, Piatelli, Gianluca, Capra, Valeria, Kitzman, Jacob O., and Meisler, Miriam H.

Published
2024
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42. Correction: Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes

Author

Martin-Almedina, Silvia, Ogmen, Kazim, Sackey, Ege, Grigoriadis, Dionysios, Karapouliou, Christina, Nadarajah, Noeline, Ebbing, Cathrine, Lord, Jenny, Mellis, Rhiannon, Kortuem, Fanny, Dinulos, Mary Beth, Polun, Cassandra, Bale, Sherri, Atton, Giles, Robinson, Alexandra, Reigstad, Hallvard, Houge, Gunnar, von der Wense, Axel, Becker, Wolf-Henning, Jeffery, Steve, Mortimer, Peter S., Gordon, Kristiana, Josephs, Katherine S., Robart, Sarah, Kilby, Mark D., Vallee, Stephanie, Gorski, Jerome L., Hempel, Maja, Berland, Siren, Mansour, Sahar, and Ostergaard, Pia

Published
2021
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43. Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features

Author

Liu, Zhigang, primary, Xin, Baozhong, additional, Smith, Iris N, additional, Sency, Valerie, additional, Szekely, Julia, additional, Alkelai, Anna, additional, Shuldiner, Alan, additional, Efthymiou, Stephanie, additional, Rajabi, Farrah, additional, Coury, Stephanie, additional, Brownstein, Catherine A, additional, Rudnik-Schöneborn, Sabine, additional, Bruel, Ange-Line, additional, Thevenon, Julien, additional, Zeidler, Shimriet, additional, Jayakar, Parul, additional, Schmidt, Axel, additional, Cremer, Kirsten, additional, Engels, Hartmut, additional, Peters, Sophia O, additional, Zaki, Maha S, additional, Duan, Ruizhi, additional, Zhu, Changlian, additional, Xu, Yiran, additional, Gao, Chao, additional, Sepulveda-Morales, Tania, additional, Maroofian, Reza, additional, Alkhawaja, Issam A, additional, Khawaja, Mariam, additional, Alhalasah, Hunaida, additional, Houlden, Henry, additional, Madden, Jill A, additional, Turchetti, Valentina, additional, Marafi, Dana, additional, Agrawal, Pankaj B, additional, Schatz, Ulrich, additional, Rotenberg, Ari, additional, Rotenberg, Joshua, additional, Mancini, Grazia M S, additional, Bakhtiari, Somayeh, additional, Kruer, Michael, additional, Thiffault, Isabelle, additional, Hirsch, Steffen, additional, Hempel, Maja, additional, Stühn, Lara G, additional, Haack, Tobias B, additional, Posey, Jennifer E, additional, Lupski, James R, additional, Lee, Hyunpil, additional, Sarn, Nicholas B, additional, Eng, Charis, additional, Gonzaga-Jauregui, Claudia, additional, Zhang, Bin, additional, and Wang, Heng, additional

Published
2023
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44. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder

Author

Rots, Dmitrijs, primary, Jakub, Taryn E., additional, Keung, Crystal, additional, Jackson, Adam, additional, Banka, Siddharth, additional, Pfundt, Rolph, additional, de Vries, Bert B.A., additional, van Jaarsveld, Richard H., additional, Hopman, Saskia M.J., additional, van Binsbergen, Ellen, additional, Valenzuela, Irene, additional, Hempel, Maja, additional, Bierhals, Tatjana, additional, Kortüm, Fanny, additional, Lecoquierre, Francois, additional, Goldenberg, Alice, additional, Hertz, Jens Michael, additional, Andersen, Charlotte Brasch, additional, Kibæk, Maria, additional, Prijoles, Eloise J., additional, Stevenson, Roger E., additional, Everman, David B., additional, Patterson, Wesley G., additional, Meng, Linyan, additional, Gijavanekar, Charul, additional, De Dios, Karl, additional, Lakhani, Shenela, additional, Levy, Tess, additional, Wagner, Matias, additional, Wieczorek, Dagmar, additional, Benke, Paul J., additional, Lopez Garcia, María Soledad, additional, Perrier, Renee, additional, Sousa, Sergio B., additional, Almeida, Pedro M., additional, Simões, Maria José, additional, Isidor, Bertrand, additional, Deb, Wallid, additional, Schmanski, Andrew A., additional, Abdul-Rahman, Omar, additional, Philippe, Christophe, additional, Bruel, Ange-Line, additional, Faivre, Laurence, additional, Vitobello, Antonio, additional, Thauvin, Christel, additional, Smits, Jeroen J., additional, Garavelli, Livia, additional, Caraffi, Stefano G., additional, Peluso, Francesca, additional, Davis-Keppen, Laura, additional, Platt, Dylan, additional, Royer, Erin, additional, Leeuwen, Lisette, additional, Sinnema, Margje, additional, Stegmann, Alexander P.A., additional, Stumpel, Constance T.R.M., additional, Tiller, George E., additional, Bosch, Daniëlle G.M., additional, Potgieter, Stephanus T., additional, Joss, Shelagh, additional, Splitt, Miranda, additional, Holden, Simon, additional, Prapa, Matina, additional, Foulds, Nicola, additional, Douzgou, Sofia, additional, Puura, Kaija, additional, Waltes, Regina, additional, Chiocchetti, Andreas G., additional, Freitag, Christine M., additional, Satterstrom, F. Kyle, additional, De Rubeis, Silvia, additional, Buxbaum, Joseph, additional, Gelb, Bruce D., additional, Branko, Aleksic, additional, Kushima, Itaru, additional, Howe, Jennifer, additional, Scherer, Stephen W., additional, Arado, Alessia, additional, Baldo, Chiara, additional, Patat, Olivier, additional, Bénédicte, Demeer, additional, Lopergolo, Diego, additional, Santorelli, Filippo M., additional, Haack, Tobias B., additional, Dufke, Andreas, additional, Bertrand, Miriam, additional, Falb, Ruth J., additional, Rieß, Angelika, additional, Krieg, Peter, additional, Spranger, Stephanie, additional, Bedeschi, Maria Francesca, additional, Iascone, Maria, additional, Josephi-Taylor, Sarah, additional, Roscioli, Tony, additional, Buckley, Michael F., additional, Liebelt, Jan, additional, Dagli, Aditi I., additional, Aten, Emmelien, additional, Hurst, Anna C.E., additional, Hicks, Alesha, additional, Suri, Mohnish, additional, Aliu, Ermal, additional, Naik, Sunil, additional, Sidlow, Richard, additional, Coursimault, Juliette, additional, Nicolas, Gaël, additional, Küpper, Hanna, additional, Petit, Florence, additional, Ibrahim, Veyan, additional, Top, Deniz, additional, Di Cara, Francesca, additional, Louie, Raymond J., additional, Stolerman, Elliot, additional, Brunner, Han G., additional, Vissers, Lisenka E.L.M., additional, Kramer, Jamie M., additional, and Kleefstra, Tjitske, additional

Published
2023
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46. Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish

Author

Patterson, Victoria, primary, Ullah, Farid, additional, Bryant, Laura, additional, Griffin, John N., additional, Sidhu, Alpa, additional, Saliganan, Sheila, additional, Blaile, Mackenzie, additional, Saenz, Margarita S., additional, Smith, Rosemarie, additional, Ellingwood, Sara, additional, Grange, Dorothy K., additional, Hu, Xuyun, additional, Mireguli, Maimaiti, additional, Luo, Yanfei, additional, Shen, Yiping, additional, Mulhern, Maureen, additional, Zackai, Elaine, additional, Ritter, Alyssa, additional, Izumi, Kosaki, additional, Hoefele, Julia, additional, Wagner, Matias, additional, Riedhammer, Korbinian M., additional, Seitz, Barbara, additional, Robin, Nathaniel H., additional, Goodloe, Dana, additional, Mignot, Cyril, additional, Keren, Boris, additional, Cox, Helen, additional, Jarvis, Joanna, additional, Hempel, Maja, additional, Gibson, Cynthia Forster, additional, Tran Mau-Them, Frederic, additional, Vitobello, Antonio, additional, Bruel, Ange-Line, additional, Sorlin, Arthur, additional, Mehta, Sarju, additional, Raymond, F. Lucy, additional, Gilmore, Kelly, additional, Powell, Bradford C., additional, Weck, Karen, additional, Li, Chumei, additional, Vulto-van Silfhout, Anneke T., additional, Giacomini, Thea, additional, Mancardi, Maria Margherita, additional, Accogli, Andrea, additional, Salpietro, Vincenzo, additional, Zara, Federico, additional, Vora, Neeta L., additional, Davis, Erica E., additional, Burdine, Rebecca, additional, and Bhoj, Elizabeth, additional

Published
2023
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47. Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Author

Schmidt, Axel, primary, Danyel, Magdalena, additional, Grundmann, Kathrin, additional, Brunet, Theresa, additional, Klinkhammer, Hannah, additional, Hsieh, Tzung-Chien, additional, Engels, Hartmut, additional, Peters, Sophia, additional, Knaus, Alexej, additional, Moosa, Shahida, additional, Averdunk, Luisa, additional, Boschann, Felix, additional, Sczakiel, Henrike, additional, Schwartzmann, Sarina, additional, Mensah, Martin Atta, additional, Pantel, Jean Tori, additional, Holtgrewe, Manuel, additional, Boesch, Annemarie, additional, Weiss, Claudia, additional, Weinhold, Natalie, additional, Suter, Aude-Annick, additional, Stoltenburg, Corinna, additional, Neugebauer, Julia, additional, Kallinich, Tillmann, additional, Kaindl, Angela M., additional, Holzhauer, Susanne, additional, Buehrer, Christoph, additional, Bufler, Philip, additional, Kornak, Uwe, additional, Ott, Claus-Eric, additional, Schuelke, Markus, additional, Nguyen, Hoa Huu Phuc, additional, Hoffjan, Sabine, additional, Grasemann, Corinna, additional, Rothoeft, Tobias, additional, Brinkmann, Folke, additional, Matar, Nora, additional, Sivalingam, Sugirthan, additional, Perne, Claudia, additional, Mangold, Elisabeth, additional, Kreiss, Martina, additional, Cremer, Kirsten, additional, Betz, Regina C., additional, Bender, Tim, additional, Muecke, Martin, additional, Grigull, Lorenz, additional, Klockgether, Thomas, additional, Isabel, Spier, additional, Heimbach, Andre, additional, Tim, Bender, additional, Brand, Fabian, additional, Stieber, Christiane, additional, Morawiec, Alexandra Marzena, additional, Karakostas, Pantelis, additional, Schaefer, Valentin S., additional, Bernsen, Sarah, additional, Weydt, Patrick, additional, Castro-Gomez, Sergio, additional, Aziz, Ahmad, additional, Grobe-Einsler, Marcus, additional, Kimmich, Okka, additional, Kobeleva, Xenia, additional, oender, Demet, additional, Lesmann, Hellen, additional, Kumar, Sheetal, additional, Tacik, Pawel, additional, Lee-Kirsch, Min Ae, additional, Berner, Reinhard, additional, Schuetz, Catharina, additional, Koerholz, Julia, additional, Kretschmer, Tanita, additional, Di Donato, Nataliya, additional, Schroeck, Evelin, additional, Heinen, Andre, additional, Reuner, Ulrike, additional, Hansske, Amalia-Mihaela, additional, Kaiser, Frank J., additional, Manka, Eva, additional, Munteanu, Martin, additional, Kuechler, Alma, additional, Cordula, Kiewert, additional, Hirtz, Raphael, additional, Schlapakow, Elena, additional, Schlein, Christian, additional, Lisfeld, Jasmin, additional, Kubisch, Christian, additional, Herget, Theresia, additional, Hempel, Maja, additional, Weiler-Normann, Christina, additional, Ullrich, Kurt, additional, Schramm, Christoph, additional, Rudolph, Cornelia, additional, Rillig, Franziska, additional, Groffmann, Maximilian, additional, Muntau, Ania, additional, Tibelius, Alexandra, additional, Schwaibold, Eva M. C., additional, Schaaf, Christian P., additional, Zawada, Michal, additional, Kaufmann, Lilian, additional, Hinderhofer, Katrin, additional, Okun, Pamela M., additional, Kotzaeridou, Urania, additional, Hoffmann, Georg F., additional, Choukair, Daniela, additional, Bettendorf, Markus, additional, Spielmann, Malte, additional, Ripke, Annekatrin, additional, Pauly, Martje, additional, Muenchau, Alexander, additional, Lohmann, Katja, additional, Huening, Irina, additional, Hanker, Britta, additional, Baeumer, Tobias, additional, Herzog, Rebecca, additional, Hellenbroich, Yorck, additional, Westphal, Dominik S., additional, Strom, Tim, additional, Kovacs, Reka, additional, Riedhammer, Korbinian M., additional, Mayerhanser, Katharina, additional, Graf, Elisabeth, additional, Brugger, Melanie, additional, Hoefele, Julia, additional, Oexle, Konrad, additional, Mirza-Schreiber, Nazanin, additional, Berutti, Riccardo, additional, Schatz, Ulrich, additional, Krenn, Martin, additional, Makowski, Christine, additional, Weigand, Heike, additional, Schroeder, Sebastian, additional, Rohlfs, Meino, additional, Katharina, Vill, additional, Hauck, Fabian, additional, Borggraefe, Ingo, additional, Mueller-Felber, Wolfgang, additional, Kurth, Ingo, additional, Elbracht, Miriam, additional, Knopp, Cordula, additional, Begemann, Matthias, additional, Kraft, Florian, additional, Lemke, Johannes, additional, Hentschel, Julia, additional, Platzer, Konrad, additional, Strehlow, Vincent, additional, Abou Jamra, Rami, additional, Kehrer, Martin, additional, Demidov, German, additional, Beck-Woedl, Stefanie, additional, Graessner, Holm, additional, Sturm, Marc, additional, Zeltner, Lena, additional, Schoels, Ludger J., additional, Magg, Janine, additional, Bevot, Andrea, additional, Kehrer, Christiane, additional, Kaiser, Nadja, additional, Horn, Denise, additional, Grueters-Kieslich, Annette, additional, Klein, Christoph, additional, Mundlos, Stefan, additional, Noethen, Markus, additional, Riess, Olaf, additional, Meitinger, Thomas, additional, Krude, Heiko, additional, Krawitz, Peter M., additional, Haack, Tobias, additional, Ehmke, Nadja, additional, and Wagner, Matias, additional

Published
2023
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48. Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

Author

Worthmann, Anna, primary, Ridder, Julius, additional, Piel, Sharlaine, additional, Evangelakos, Ioannis, additional, Musfeldt, Melina, additional, Voß, Hannah, additional, O'Farell, Marie, additional, Fischer, Alexander, additional, Adak, Sangeeta, additional, Sundd, Monica, additional, Siffeti, Hasibullah, additional, Haumann, Friederike, additional, Kloth, Katja, additional, Bierhals, Tatjana, additional, Heine, Markus, additional, Pertzborn, Paul, additional, Pauly, Mira, additional, Scholz, Julia-Josefine, additional, Kundu, Suman, additional, Fuh, Manka, additional, Neu, Axel, additional, Tödter, Klaus, additional, Hempel, Maja, additional, Knippschild, Uwe, additional, Semenkovich, Clay, additional, Schlüter, Hartmut, additional, Heeren, Joerg, additional, Scheja, Ludger, additional, Kubisch, Christian, additional, and Schlein, Christian, additional

Published
2023
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49. The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1

Author

Park, Julien H., Nordström, Ulrika, Tsiakas, Konstantinos, Keskin, Isil, Elpers, Christiane, Mannil, Manoj, Heller, Raoul, Nolan, Melinda, Alburaiky, Salam, Zetterström, Per, Hempel, Maja, Schara-Schmidt, Ulrike, Biskup, Saskia, Steinacker, Petra, Otto, Markus, Weishaupt, Jochen, Hahn, Andreas, Santer, Rene, Marquardt, Thorsten, Marklund, Stefan L., Andersen, Peter M., Park, Julien H., Nordström, Ulrika, Tsiakas, Konstantinos, Keskin, Isil, Elpers, Christiane, Mannil, Manoj, Heller, Raoul, Nolan, Melinda, Alburaiky, Salam, Zetterström, Per, Hempel, Maja, Schara-Schmidt, Ulrike, Biskup, Saskia, Steinacker, Petra, Otto, Markus, Weishaupt, Jochen, Hahn, Andreas, Santer, Rene, Marquardt, Thorsten, Marklund, Stefan L., and Andersen, Peter M.

Abstract

Superoxide dismutase-1 is a ubiquitously expressed antioxidant enzyme. Mutations in SOD1 can cause amyotrophic lateral sclerosis, probably via a toxic gain-of-function involving protein aggregation and prion-like mechanisms. Recently, homozygosity for loss-of-function mutations in SOD1 has been reported in patients presenting with infantile-onset motor neuron disease. We explored the bodily effects of superoxide dismutase-1 enzymatic deficiency in eight children homozygous for the p.C112Wfs∗11 truncating mutation. In addition to physical and imaging examinations, we collected blood, urine and skin fibroblast samples. We used a comprehensive panel of clinically established analyses to assess organ function and analysed oxidative stress markers, antioxidant compounds, and the characteristics of the mutant Superoxide dismutase-1. From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage. The disease progression seemed to slow down over the following years. The p.C112Wfs∗11 gene product is unstable, rapidly degraded and no aggregates were found in fibroblast. Most laboratory tests indicated normal organ integrity and only a few modest deviations were found. The patients displayed anaemia with shortened survival of erythrocytes containing decreased levels of reduced glutathione. A variety of other antioxidants and oxidant damage markers were within normal range. In conclusion, non-neuronal organs in humans show a remarkable tolerance to absence of Superoxide dismutase-1 enzymatic activity. The study highlights the enigmatic specific vulnerability of the motor system to both gain-of-function mutations in SOD1 and loss of the enzyme as in the here depicted infantile superoxide dismutase-1 deficiency syndrome.

Published
2023
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50. AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia

Author

CMM Groep Maurice, Cancer, DT Schildpad, Integrale & Alg. Kindergen Patientenzorg, Other research (not in main researchprogram), Pathologie Pathologen staf, Regenerative Medicine and Stem Cells, Terhal, Paulien, Venhuizen, Anton J, Lessel, Davor, Tan, Wen-Hann, Alswaid, Abdulrahman, Grün, Regina, Alzaidan, Hamad I, von Kroge, Simon, Ragab, Nada, Hempel, Maja, Kubisch, Christian, Novais, Eduardo, Cristobal, Alba, Tripolszki, Kornelia, Bauer, Peter, Fischer-Zirnsak, Björn, Nievelstein, Rutger A J, van Dijk, Atty, Nikkels, Peter, Oheim, Ralf, Hahn, Heidi, Bertoli-Avella, Aida, Maurice, Madelon M, Kornak, Uwe, CMM Groep Maurice, Cancer, DT Schildpad, Integrale & Alg. Kindergen Patientenzorg, Other research (not in main researchprogram), Pathologie Pathologen staf, Regenerative Medicine and Stem Cells, Terhal, Paulien, Venhuizen, Anton J, Lessel, Davor, Tan, Wen-Hann, Alswaid, Abdulrahman, Grün, Regina, Alzaidan, Hamad I, von Kroge, Simon, Ragab, Nada, Hempel, Maja, Kubisch, Christian, Novais, Eduardo, Cristobal, Alba, Tripolszki, Kornelia, Bauer, Peter, Fischer-Zirnsak, Björn, Nievelstein, Rutger A J, van Dijk, Atty, Nikkels, Peter, Oheim, Ralf, Hahn, Heidi, Bertoli-Avella, Aida, Maurice, Madelon M, and Kornak, Uwe

Published
2023

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