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JOURNAL ARTICLE
Alessa R Ringel, Quentin Szabo, Andrea M Chiariello, Konrad Chudzik, Robert Schöpflin, Patricia Rothe, Alexandra L Mattei, Tobias Zehnder, Dermot Harnett, Verena Laupert, Simona Bianco, Sara Hetzel, Juliane Glaser, Mai H Q Phan, Magdalena Schindler, Daniel M Ibrahim, Christina Paliou, Andrea Esposito, Cesar A Prada-Medina, Stefan A Haas, Peter Giere, Martin Vingron, Lars Wittler, Alexander Meissner, Mario Nicodemi, Giacomo Cavalli, Frédéric Bantignies, Stefan Mundlos, Michael I Robson
Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression...
September 29, 2022: Cell
#22
JOURNAL ARTICLE
Jan Berghöfer, Nadia Khaveh, Stefan Mundlos, Julia Metzger
BACKGROUND: Past selection events left footprints in the genome of domestic animals, which can be traced back by stretches of homozygous genotypes, designated as runs of homozygosity (ROHs). The analysis of common ROH regions within groups or populations displaying potential signatures of selection requires high-quality SNP data as well as carefully adjusted ROH-defining parameters. In this study, we used a simultaneous testing of rule- and model-based approaches to perform strategic ROH calling in genomic data from different pig populations to detect genomic regions under selection for specific phenotypes...
August 6, 2022: BMC Genomics
#23
JOURNAL ARTICLE
Uwe Kornak, Namrata Saha, Boris Keren, Alexander Neumann, Ana Lisa Taylor Tavares, Juliette Piard, Johannes Kopp, João Guilherme Rodrigues Alves, Miguel Rodríguez de Los Santos, Naji El Choubassi, Nadja Ehmke, Marten Jäger, Malte Spielmann, Jean Tori Pantel, Elodie Lejeune, Beatrix Fauler, Thorsten Mielke, Jochen Hecht, David Meierhofer, Tim M Strom, Vincent Laugel, Alexis Brice, Stefan Mundlos, Aida Bertoli-Avella, Peter Bauer, Florian Heyd, Odile Boute, Juliette Dupont, Christel Depienne, Lionel Van Maldergem, Björn Fischer-Zirnsak
PURPOSE: In this study we aimed to identify the molecular genetic cause of a progressive multisystem disease with prominent lipodystrophy. METHODS: In total, 5 affected individuals were investigated using exome sequencing. Dermal fibroblasts were characterized using RNA sequencing, proteomics, immunoblotting, immunostaining, and electron microscopy. Subcellular localization and rescue studies were performed. RESULTS: We identified a lipodystrophy phenotype with a typical facial appearance, corneal clouding, achalasia, progressive hearing loss, and variable severity...
June 6, 2022: Genetics in Medicine: Official Journal of the American College of Medical Genetics
#24
JOURNAL ARTICLE
Franziska Rillig, Annette Grüters, Tobias Bäumer, Georg F Hoffmann, Daniela Choukair, Reinhard Berner, Min Ae Lee-Kirsch, Martin Mücke, Corinna Grasemann, Annekatrin Ripke, Lena Zeltner, Gabriele Müller, Monika Glauch, Holm Graessner, Fabian Hauck, Christoph Klein, Markus M Nöthen, Olaf Riess, Stefan Mundlos, Thomas Meitinger, Tobias Kurt, Kerstin L Wainwright, Jochen Schmitt, Christoph Schramm, Heiko Krude
BACKGROUND: Patients with rare diseases often undergo a diagnostic odyssey that can last many years until the diagnosis is definitively established. To improve the diagnosis and treatment of these patients, the German National Task Force for Patients With Rare Diseases (Nationales Aktionsbündnis für Menschen mit Seltenen Erkrankungen, NAMSE) has recommended the creation of Rare Disease Centers (RDCs). METHODS: As part of the joint Translate-NAMSE project, sponsored by the G-BA Innovation Fund (G-BA, German Federal Joint Committee), we investigated the performance of RDCs in establishing the diagnosis of patients suspected to have a rare disease...
July 11, 2022: Deutsches Ärzteblatt International
#25
JOURNAL ARTICLE
Katerina Kraft, Kathryn E Yost, Sedona E Murphy, Andreas Magg, Yicheng Long, M Ryan Corces, Jeffrey M Granja, Lars Wittler, Stefan Mundlos, Thomas R Cech, Alistair N Boettiger, Howard Y Chang
SignificanceThe relationship between long-range Polycomb-associated chromatin contacts and the linear propagation of histone H3 lysine 27 trimethylation (H3K27me3) by Polycomb repressive complex 2 (PRC2) is not well-characterized. Here, we nominate a role for developmental loci as genomic architectural elements that enable long-range spreading of H3K27me3. Polycomb-associated loops are disrupted upon loss of PRC2 binding and deletion of loop anchors results in alterations of H3K27me3 deposition and ectopic gene expression...
May 31, 2022: Proceedings of the National Academy of Sciences of the United States of America
#26
JOURNAL ARTICLE
Francisca M Real, Miguel Lao-Pérez, Miguel Burgos, Stefan Mundlos, Darío G Lupiáñez, Rafael Jiménez, Francisco J Barrionuevo
In species with seasonal breeding, male specimens undergo substantial testicular regression during the nonbreeding period of the year. However, the molecular mechanisms that control this biological process are largely unknown. Here, we report a transcriptomic analysis on the Iberian mole, Talpa occidentalis, in which the desquamation of live, nonapoptotic germ cells is the major cellular event responsible for testis regression. By comparing testes at different reproductive states (active, regressing, and inactive), we demonstrate that the molecular pathways controlling the cell adhesion function in the seminiferous epithelium, such as the MAPK, ERK, and TGF-β signaling, are altered during the regression process...
May 10, 2022: Journal of Experimental Zoology. Part B, Molecular and Developmental Evolution
#27
JOURNAL ARTICLE
Tzung-Chien Hsieh, Aviram Bar-Haim, Shahida Moosa, Nadja Ehmke, Karen W Gripp, Jean Tori Pantel, Magdalena Danyel, Martin Atta Mensah, Denise Horn, Stanislav Rosnev, Nicole Fleischer, Guilherme Bonini, Alexander Hustinx, Alexander Schmid, Alexej Knaus, Behnam Javanmardi, Hannah Klinkhammer, Hellen Lesmann, Sugirthan Sivalingam, Tom Kamphans, Wolfgang Meiswinkel, Frédéric Ebstein, Elke Krüger, Sébastien Küry, Stéphane Bézieau, Axel Schmidt, Sophia Peters, Hartmut Engels, Elisabeth Mangold, Martina Kreiß, Kirsten Cremer, Claudia Perne, Regina C Betz, Tim Bender, Kathrin Grundmann-Hauser, Tobias B Haack, Matias Wagner, Theresa Brunet, Heidi Beate Bentzen, Luisa Averdunk, Kimberly Christine Coetzer, Gholson J Lyon, Malte Spielmann, Christian P Schaaf, Stefan Mundlos, Markus M Nöthen, Peter M Krawitz
Many monogenic disorders cause a characteristic facial morphology. Artificial intelligence can support physicians in recognizing these patterns by associating facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this 'supervised' approach means that diagnoses are only possible if the disorder was part of the training set. To improve recognition of ultra-rare disorders, we developed GestaltMatcher, an encoder for portraits that is based on a deep convolutional neural network...
March 2022: Nature Genetics
#28
JOURNAL ARTICLE
Felix Boschann, Daniel Acero Moreno, Martin A Mensah, Henrike L Sczakiel, Karolina Skipalova, Manuel Holtgrewe, Stefan Mundlos, Björn Fischer-Zirnsak
Bilateral laryngeal abductor paralysis is a rare entity and the second most common cause of stridor in newborns. So far, no conclusive genetic or chromosomal aberration has been reported for X-linked isolated bilateral vocal cord paralysis, also referred to as Plott syndrome. Via whole genome sequencing (WGS), we identified a complex interchromosomal insertion in a large family with seven affected males. The 404 kb inserted fragment originates from chromosome 10q21.3, contains no genes and is inserted inversionally into the intergenic chromosomal region Xq27...
January 31, 2022: Journal of Human Genetics
#29
JOURNAL ARTICLE
Helle Lybaek, Michael Robson, Nicole de Leeuw, Jayne Y Hehir-Kwa, Aaron Jeffries, Bjørn Ivar Haukanes, Siren Berland, Diederik de Bruijn, Stefan Mundlos, Malte Spielmann, Gunnar Houge
LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern...
March 2022: Autism Research: Official Journal of the International Society for Autism Research
#30
Bruno Reversade, Nathalie Escande-Beillard, Aikaterini Dimopoulou, Björn Fischer, Serene C Chng, Yun Li, Mohammad Shboul, Puay-Yoke Tham, Hülya Kayserili, Lihadh Al-Gazali, Monzer Shahwan, Francesco Brancati, Hane Lee, Brian D O'Connor, Mareen Schmidt-von Kegler, Barry Merriman, Stanley F Nelson, Amira Masri, Fawaz Alkazaleh, Deanna Guerra, Paola Ferrari, Arti Nanda, Anna Rajab, David Markie, Mary Gray, John Nelson, Arthur Grix, Annemarie Sommer, Ravi Savarirayan, Andreas R Janecke, Elisabeth Steichen, David Sillence, Ingrid Haußer, Birgit Budde, Gudrun Nürnberg, Peter Nürnberg, Petra Seemann, Désirée Kunkel, Giovanna Zambruno, Bruno Dallapiccola, Markus Schuelke, Stephen Robertson, Hanan Hamamy, Bernd Wollnik, Lionel Van Maldergem, Stefan Mundlos, Uwe Kornak
No abstract text is available yet for this article.
February 2022: Nature Genetics
#31
JOURNAL ARTICLE
Rutger A F Gjaltema, Till Schwämmle, Pauline Kautz, Michael Robson, Robert Schöpflin, Liat Ravid Lustig, Lennart Brandenburg, Ilona Dunkel, Carolina Vechiatto, Evgenia Ntini, Verena Mutzel, Vera Schmiedel, Annalisa Marsico, Stefan Mundlos, Edda G Schulz
Developmental genes such as Xist, which initiates X chromosome inactivation, are controlled by complex cis-regulatory landscapes, which decode multiple signals to establish specific spatiotemporal expression patterns. Xist integrates information on X chromosome dosage and developmental stage to trigger X inactivation in the epiblast specifically in female embryos. Through a pooled CRISPR screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements of Xist at the onset of random X inactivation...
January 6, 2022: Molecular Cell
#32
JOURNAL ARTICLE
King L Hung, Kathryn E Yost, Liangqi Xie, Quanming Shi, Konstantin Helmsauer, Jens Luebeck, Robert Schöpflin, Joshua T Lange, Rocío Chamorro González, Natasha E Weiser, Celine Chen, Maria E Valieva, Ivy Tsz-Lo Wong, Sihan Wu, Siavash R Dehkordi, Connor V Duffy, Katerina Kraft, Jun Tang, Julia A Belk, John C Rose, M Ryan Corces, Jeffrey M Granja, Rui Li, Utkrisht Rajkumar, Jordan Friedlein, Anindya Bagchi, Ansuman T Satpathy, Robert Tjian, Stefan Mundlos, Vineet Bafna, Anton G Henssen, Paul S Mischel, Zhe Liu, Howard Y Chang
Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1 . Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3 . Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours...
December 2021: Nature
#33
JOURNAL ARTICLE
Marie Coutelier, Manuel Holtgrewe, Marten Jäger, Ricarda Flöttman, Martin A Mensah, Malte Spielmann, Peter Krawitz, Denise Horn, Dieter Beule, Stefan Mundlos
Copy Number Variants (CNVs) are deletions, duplications or insertions larger than 50 base pairs. They account for a large percentage of the normal genome variation and play major roles in human pathology. While array-based approaches have long been used to detect them in clinical practice, whole-genome sequencing (WGS) bears the promise to allow concomitant exploration of CNVs and smaller variants. However, accurately calling CNVs from WGS remains a difficult computational task, for which a consensus is still lacking...
February 2022: European Journal of Human Genetics: EJHG
#34
JOURNAL ARTICLE
Henrike Lisa Sczakiel, Wiebke Hülsemann, Manuel Holtgrewe, Angela Teresa Abad-Perez, Jonas Elsner, Sarina Schwartzmann, Denise Horn, Malte Spielmann, Stefan Mundlos, Martin Atta Mensah
Loss of function variants of GLI3 are associated with a variety of forms of polysyndactyly: Pallister-Hall syndrome (PHS), Greig-Cephalopolysyndactyly syndrome (GCPS), and isolated polysyndactyly (IPD). Variants affecting the N-terminal and C-terminal thirds of the GLI3 protein have been associated with GCPS, those within the central third with PHS. Cases of IPD have been attributed to variants affecting the C-terminal third of the GLI3 protein. In this study, we further investigate these genotype-phenotype correlations...
December 2021: Clinical Genetics
#35
JOURNAL ARTICLE
Uirá Souto Melo, Juliette Piard, Björn Fischer-Zirnsak, Marius-Konstantin Klever, Robert Schöpflin, Martin Atta Mensah, Manuel Holtgrewe, Francine Arbez-Gindre, Alain Martin, Virginie Guigue, Dominique Gaillard, Emilie Landais, Virginie Roze, Valerie Kremer, Rajeev Ramanah, Christelle Cabrol, Frederike L Harms, Uwe Kornak, Malte Spielmann, Stefan Mundlos, Lionel Van Maldergem
During human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family...
October 2021: Human Genetics
#36
JOURNAL ARTICLE
Magdalena Socha, Anna Sowińska-Seidler, Uirá Souto Melo, Bjørt K Kragesteen, Martin Franke, Verena Heinrich, Robert Schöpflin, Inga Nagel, Nicolas Gruchy, Stefan Mundlos, Varun K A Sreenivasan, Cristina López, Martin Vingron, Ewelina Bukowska-Olech, Malte Spielmann, Aleksander Jamsheer
Copy-number variations (CNVs) are a common cause of congenital limb malformations and are interpreted primarily on the basis of their effect on gene dosage. However, recent studies show that CNVs also influence the 3D genome chromatin organization. The functional interpretation of whether a phenotype is the result of gene dosage or a regulatory position effect remains challenging. Here, we report on two unrelated families with individuals affected by bilateral hypoplasia of the femoral bones, both harboring de novo duplications on chromosome 10q24...
September 2, 2021: American Journal of Human Genetics
#37
JOURNAL ARTICLE
Julia Körholz, Anastasia Gabrielyan, John M Sowerby, Felix Boschann, Lan-Sun Chen, Diana Paul, David Brandt, Janina Kleymann, Martin Kolditz, Nicole Toepfner, Ralf Knöfler, Eva-Maria Jacobsen, Christine Wolf, Karsten Conrad, Nadja Röber, Min Ae Lee-Kirsch, Kenneth G C Smith, Stefan Mundlos, Reinhard Berner, Alexander H Dalpke, Catharina Schuetz, William Rae
Background: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. Objective: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency...
2021: Frontiers in Immunology
#38
JOURNAL ARTICLE
Guido Vogt, Sarah Verheyen, Sarina Schwartzmann, Nadja Ehmke, Cornelia Potratz, Anette Schwerin-Nagel, Barbara Plecko, Manuel Holtgrewe, Dominik Seelow, Jasmin Blatterer, Michael R Speicher, Uwe Kornak, Denise Horn, Stefan Mundlos, Björn Fischer-Zirnsak, Felix Boschann
BACKGROUND: Genes implicated in the Golgi and endosomal trafficking machinery are crucial for brain development, and mutations in them are particularly associated with postnatal microcephaly (POM). METHODS: Exome sequencing was performed in three affected individuals from two unrelated consanguineous families presenting with delayed neurodevelopment, intellectual disability of variable degree, POM and failure to thrive. Patient-derived fibroblasts were tested for functional effects of the variants...
July 2022: Journal of Medical Genetics
#39
REVIEW
Juliane Glaser, Stefan Mundlos
One of the most fundamental questions in developmental biology is how one fertilized cell can give rise to a fully mature organism and how gene regulation governs this process. Precise spatiotemporal gene expression is required for development and is believed to be achieved through a complex interplay of sequence-specific information, epigenetic modifications, trans -acting factors, and chromatin folding. Here we review the role of chromatin folding during development, the mechanisms governing 3D genome organization, and how it is established in the embryo...
May 27, 2022: Cold Spring Harbor Perspectives in Biology
#40
JOURNAL ARTICLE
Jonas Elsner, Martin A Mensah, Manuel Holtgrewe, Jakob Hertzberg, Stefania Bigoni, Andreas Busche, Marie Coutelier, Deepthi C de Silva, Nursel Elçioglu, Isabel Filges, Erica Gerkes, Katta M Girisha, Luitgard Graul-Neumann, Aleksander Jamsheer, Peter Krawitz, Ingo Kurth, Susanne Markus, Andre Megarbane, André Reis, Miriam S Reuter, Daniel Svoboda, Christopher Teller, Beyhan Tuysuz, Seval Türkmen, Meredith Wilson, Rixa Woitschach, Inga Vater, Almuth Caliebe, Wiebke Hülsemann, Denise Horn, Stefan Mundlos, Malte Spielmann
The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing...
August 2021: Human Genetics
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