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

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...

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Bibliographic Details
Published in:Human genetics 2017-03, Vol.136 (3), p.307-320
Main Authors: Parenti, Ilaria, Teresa-Rodrigo, María E., Pozojevic, Jelena, Ruiz Gil, Sara, Bader, Ingrid, Braunholz, Diana, Bramswig, Nuria C., Gervasini, Cristina, Larizza, Lidia, Pfeiffer, Lutz, Ozkinay, Ferda, Ramos, Feliciano, Reiz, Benedikt, Rittinger, Olaf, Strom, Tim M., Watrin, Erwan, Wendt, Kerstin, Wieczorek, Dagmar, Wollnik, Bernd, Baquero-Montoya, Carolina, Pié, Juan, Deardorff, Matthew A., Gillessen-Kaesbach, Gabriele, Kaiser, Frank J.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Biomedical and Life Sciences
Biomedicine
Child
Child, Preschool
Chromatin
Chromatin - physiology
De Lange syndrome
De Lange Syndrome - genetics
Facies
Female
Gene expression
Gene Function
Genes
Genetic aspects
Genetics
Genomics
Human Genetics
Humans
Intellectual disabilities
Life Sciences
Male
Medical schools
Medicine
Metabolic Diseases
Molecular Medicine
Mutation
Original Investigation
Pediatrics
Phenotype
Phenotypes
RNA polymerase
Transcription (Genetics)
Yeast
Young Adult
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Summary: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.
ISSN:0340-6717
1432-1203
DOI:10.1007/s00439-017-1758-y