title: Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.
abstract: The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Parenti
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.|Unit of Clinical Genetics and Functional Genomics, Department of Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.
authors.forename: María E
authors.initials: ME
authors.lastname: Teresa-Rodrigo
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Pozojevic
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Ruiz Gil
authors.affiliation: Clinical Genetics Unit, Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bader
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.|German Cancer Consortium (DKTK), Deutsches Krebsforschungszentrum (DKFZ), Partner Site Berlin, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Braunholz
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Nuria C
authors.initials: NC
authors.lastname: Bramswig
authors.affiliation: Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
authors.affiliation: Arztpraxis Medizinische Genetik im Medizin Zentrum Lichtenberg-MZL, Berlin, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Pfeiffer
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Ege University, Izmir, Turkey.|Division of Pediatric Genetics, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey.
authors.forename: Ferda
authors.initials: F
authors.lastname: Ozkinay
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.|Clinical Genetics Unit, Service of Paediatrics, Hospital "Lozano Blesa" Medical School, University of Zaragoza, CIBERER-GCV and IIS-Aragón, Zaragoza, Spain.
authors.forename: Feliciano
authors.initials: F
authors.lastname: Ramos
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Reiz
authors.affiliation: Clinical Genetics Unit, Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Olaf
authors.initials: O
authors.lastname: Rittinger
authors.affiliation: Institute of Human Genetics, Technische Universität München, München, Germany.|German Research Center for Environmental Health, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Faculté de Médecine, Institut de Génétique et Développement de Rennes, Rennes, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Watrin
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wendt
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institut für Humangenetik, Universität Göttingen, Göttingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.affiliation: Department of Pediatrics, Hospital Pablo Tobon Uribe, Medellín, Colombia.
authors.forename: Carolina
authors.initials: C
authors.lastname: Baquero-Montoya
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.|Unit of Clinical Genetics and Functional Genomics, Department of Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Pié
authors.affiliation: Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.affiliation: Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. Frank.Kaiser@uksh.de.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000502:physiology*; D003635:De Lange Syndrome / Q000235:genetics*; D019066:Facies; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D055815:Young Adult
chemical_list: D002843:Chromatin