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Hum Genet. 2017 Mar;136(3):307-320. doi: 10.1007/s00439-017-1758-y. Epub 2017 Jan 24.

Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

Author information

1
Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
2
Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.
3
Unit of Clinical Genetics and Functional Genomics, Department of Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.
4
Clinical Genetics Unit, Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
5
German Cancer Consortium (DKTK), Deutsches Krebsforschungszentrum (DKFZ), Partner Site Berlin, Charité University Hospital Berlin, Berlin, Germany.
6
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
7
Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
8
Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
9
Arztpraxis Medizinische Genetik im Medizin Zentrum Lichtenberg-MZL, Berlin, Germany.
10
Department of Medical Genetics, Faculty of Medicine, Ege University, Izmir, Turkey.
11
Division of Pediatric Genetics, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey.
12
Clinical Genetics Unit, Service of Paediatrics, Hospital "Lozano Blesa" Medical School, University of Zaragoza, CIBERER-GCV and IIS-Aragón, Zaragoza, Spain.
13
Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany.
14
Institute of Human Genetics, Technische Universität München, München, Germany.
15
German Research Center for Environmental Health, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
16
Faculté de Médecine, Institut de Génétique et Développement de Rennes, Rennes, France.
17
Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
18
Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
19
Institut für Humangenetik, Universität Göttingen, Göttingen, Germany.
20
Department of Pediatrics, Hospital Pablo Tobon Uribe, Medellín, Colombia.
21
Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
22
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
23
Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
24
Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. Frank.Kaiser@uksh.de.

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.

PMID:
28120103
DOI:
10.1007/s00439-017-1758-y
[Indexed for MEDLINE]

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