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.

Chromatinopathies: A focus on Cornelia de Lange syndrome

“…Moreover, multiple next‐generation sequencing (NGS) technologies identified mutations in key chromatin‐associated factors, genetically different from cohesin, in patients presenting features of CdLS or CdLS‐like phenotype. These mutations affect genes coding for methyltransferases such as KMT2A , for subunits of the chromatin‐remodeler SWItch/sucrose non‐fermentable (SWI/SNF) complex and for transcriptional regulators such as EP300 , AFF4 , ANKRD11 , SETD5 or the Bromodomain‐containing protein 4 BRD4 gene, encoding a chromatin‐associated protein . In Figure the facial dysmorphisms associated with the genes mentioned above are shown and clinical features associated with mutations in these genes are summarized in Table .…”

“…Classical facial dysmorphisms of CdLS and related overlapping syndromes. Patient's representation in the middle of the figure displays typical CdLS phenotype with mutations in NIPBL (representative of classic CdLS dysmorphisms); all the other patients' representations surrounding NIPBL display all the related phenotypic variants that overlap with the classic CdLS: AFF4 , ANKRD11 , KMT2A , SETD5 , EP300 , BRD4 , SWI/SNF . CdLS, Cornelia de Lange syndrome [Colour figure can be viewed at wileyonlinelibrary.com]…”

“…SETD5 is a chromatin‐regulatory protein involved in transcriptional regulation. In the pioneer work by Parenti and colleagues, the two described patients showed some CdLS classical features combined with typical SETD5 phenotypical presentation (ie, intellectual disability, short stature, microcephaly, hypotonia and heart defects), opening the possibility of a wider clinical presentation of CdLS patients with variants in SETD5 …”

“…The phenotype of CdLS‐like patients can overlap with features characteristic for other syndromes, typically chromatin disorders . Reciprocally, patients with diagnosis of chromatin disorders (eg, WDSTS, RSTS, CSS) can present with clinical signs characteristic for CdLS . Clinical diagnosis of these cases is often challenging or rather impossible without genetic evidence.…”

“…The clinical overlap among CdLS and other chromatin disorders can be explained molecularly by the functional network between cohesin and other chromatin‐associated complexes that might lead to alterations in the expression of overlapping genes and proteins networks. Indeed, it is conceivable that mutations in cohesin or chromatin remodelers impair a common protein network and are therefore responsible for a similar, albeit wide, clinical presentation called “CdLS‐spectrum.”…”