scholarly journals Cornelia de Lange Syndrome as Paradigm of Chromatinopathies

2021 ◽  
Vol 15 ◽  
Author(s):  
Ilaria Parenti ◽  
Frank J. Kaiser
Keyword(s):  
Transcriptional Regulation ◽  
Chromatin Remodeling ◽  
Neurodevelopmental Disorders ◽  
Molecular Mechanisms ◽  
Cornelia De Lange Syndrome ◽  
Facial Dysmorphism ◽  
Behavioral Disturbances ◽  
Chromatid Cohesion ◽  
Topologically Associated Domains ◽  
Cornelia De Lange

Chromatinopathies can be defined as a class of neurodevelopmental disorders caused by mutations affecting proteins responsible for chromatin remodeling and transcriptional regulation. The resulting dysregulation of gene expression favors the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disturbances. Cornelia de Lange syndrome (CdLS) is a prime example of a chromatinopathy. It is caused by mutations affecting subunits or regulators of the cohesin complex, a multisubunit protein complex involved in various molecular mechanisms such as sister chromatid cohesion, transcriptional regulation and formation of topologically associated domains. However, disease-causing variants in non-cohesin genes with overlapping functions have also been described in association with CdLS. Notably, the majority of these genes had been previously found responsible for distinct neurodevelopmental disorders that also fall within the category of chromatinopathies and are frequently considered as differential diagnosis for CdLS. In this review, we provide a systematic overview of the current literature to summarize all mutations in non-cohesin genes identified in association with CdLS phenotypes and discuss about the interconnection of proteins belonging to the chromatinopathies network.

scholarly journals BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Pablo García-Gutiérrez ◽  
Mario García-Domínguez
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Complex Function ◽  
Clinical Manifestations ◽  
Cornelia De Lange Syndrome ◽  
Cohesin Complex ◽  
Developmental Defects ◽  
Cornelia De Lange

Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered a cohesinopathy together with other phenotypically related diseases because of their association with mutations in subunits of the cohesin complex. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably and, although their precise molecular mechanisms are not well defined yet, the potential pathomechanisms underlying these diverse developmental defects have been theoretically linked to alterations of the cohesin complex function. The cohesin complex plays a critical role in sister chromatid cohesion, but this function is not affected in CdLS. In the last decades, a non-cohesion-related function of this complex on transcriptional regulation has been well established and CdLS pathoetiology has been recently associated to gene expression deregulation. Up to 70% of CdLS cases are linked to mutations in the cohesin-loading factor NIPBL, which has been shown to play a prominent function on chromatin architecture and transcriptional regulation. Therefore, it has been suggested that CdLS can be considered a transcriptomopathy. Actually, CdLS-like phenotypes have been associated to mutations in chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most of which have no known direct association with cohesin. In the case of BRD4, a critical highly investigated transcriptional coregulator, an interaction with NIPBL has been recently revealed, providing evidence on their cooperation in transcriptional regulation of developmentally important genes. This new finding reinforces the notion of an altered gene expression program during development as the major etiological basis for CdLS. In this review, we intend to integrate the recent available evidence on the molecular mechanisms underlying the clinical manifestations of CdLS, highlighting data that favors a transcription-centered framework, which support the idea that CdLS could be conceptualized as a transcriptomopathy.

scholarly journals Diagnosing Cornelia de Lange syndrome and related neurodevelopmental disorders using RNA sequencing

2020 ◽  
Vol 22 (5) ◽  
pp. 927-936 ◽  
Author(s):  
Stefan Rentas ◽  
Komal S. Rathi ◽  
Maninder Kaur ◽  
Pichai Raman ◽  
Ian D. Krantz ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Neurodevelopmental Disorders ◽  
Cornelia De Lange Syndrome ◽  
Cornelia De Lange

scholarly journals Classical Cornelia de Lange syndrome in a neonate

2021 ◽  
Vol 9 (12) ◽  
pp. 3710
Author(s):  
Abdul Tawab ◽  
Madhu George ◽  
Ann Mary Zacharias
Keyword(s):  
Developmental Disorder ◽  
Cornelia De Lange Syndrome ◽  
Heterozygous Mutation ◽  
Facial Dysmorphism ◽  
Preterm Newborn ◽  
Cardiac Defects ◽  
Multiple Systems ◽  
Limb Deformities ◽  
Cornelia De Lange ◽  
Gastrointestinal Abnormalities

Cornelia de Lange syndrome is a rare developmental disorder syndrome involving multiple systems characterized by facial dysmorphism limb deformities, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. The features of this disorder range from mild to severe.  We present here a case of preterm newborn with Classical Cornelia de Lange syndrome with heterozygous mutation in NIBPL gene.

Cornelia De Lange Syndrome in Iraq

2020 ◽  
Vol 2 (02) ◽  
pp. 01-04
Author(s):  
Aamir Mosawi
Keyword(s):  
Mental Retardation ◽  
Male Patient ◽  
Growth Retardation ◽  
Cornelia De Lange Syndrome ◽  
Facial Dysmorphism ◽  
Upper Lip ◽  
Nasal Bridge ◽  
Short Nose ◽  
Convergent Squint ◽  
Cornelia De Lange

Background: Cornelia de Lange syndrome is a rare syndrome of highly variable phenotype making a spectrum ranging from classic syndrome with many cardinal features to mild condition few cardinal features. Typically patients with classic syndrome had growth and mental retardation and distinctive facial dysmorphism including thick (bushy) and / or long eyebrows commonly with synophrys, short nose with depressed or concave nasal bridge and/or upturned nasal tip , long or smooth or indistinct philtrum, thin upper lip vermilion and/or downturned corners of mouth, and low set ears. The diagnosis of the syndrome is clinical. Ocular abnormalities that can be associated with Cornelia de Lang syndrome squint, nystagmus, refractive errors, and ptosis. Materials and methods: The occurrence of Cornelia de Lange syndrome has not been reported or well-documented. The first four Iraqi patients (Three boys and one girl) with Cornelia de Lange syndrome are described. The relevant literatures were reviewed with aim of determining the early documentation of the syndrome in the medical literatures. Results: All the patients were sporadic cases and had growth retardation, severe mental retardation with significant developmental delay, thick eye brows with some degree of synophrys, short nose with depressed or concave nasal bridge, and low set ears. All the patients had normal karyotype. One male patient had all of the classical features including long smooth and indistinct philtrum, thin upper lip vermilion, and downturned corners of mouth. The second male patient had a concave nasal bridge that becomes more obvious during crying, nystagmus and bilateral convergent squint. The third boy had milder dysmorphic features. The fourth patient was a girl who was the second of a twin. She had severe growth retardation and was hypotonic with poor head control. She also had bilateral convergent squint, refractive error, and reduction in visual acuity. Conclusion: The first four Iraqi patients with Cornelia de Lang syndrome are reported.

scholarly journals NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome

2004 ◽  
Vol 36 (6) ◽  
pp. 636-641 ◽  
Author(s):  
Emma T Tonkin ◽  
Tzu-Jou Wang ◽  
Steven Lisgo ◽  
Michael J Bamshad ◽  
Tom Strachan
Keyword(s):  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Cornelia De Lange Syndrome ◽  
Chromatid Cohesion ◽  
Cornelia De Lange

scholarly journals Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Patricia Garcia ◽  
Rita Fernandez-Hernandez ◽  
Ana Cuadrado ◽  
Ignacio Coca ◽  
Antonio Gomez ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Molecular Mechanisms ◽  
Cpg Islands ◽  
Gc Content ◽  
Wide Distribution ◽  
Cornelia De Lange Syndrome ◽  
Multiple Organs ◽  
Genome Wide ◽  
Distribution Studies ◽  
Cornelia De Lange

AbstractCornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF.

scholarly journals Diagnosing Cornelia de Lange syndrome and related neurodevelopmental disorders using RNA-sequencing

2019 ◽  
Author(s):  
Stefan Rentas ◽  
Komal S. Rathi ◽  
Maninder Kaur ◽  
Pichai Raman ◽  
Ian D. Krantz ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Neurodevelopmental Disorders ◽  
Diagnostic Testing ◽  
Tissue Expression ◽  
Cornelia De Lange Syndrome ◽  
Rna Seq ◽  
Genetic Syndromes ◽  
Gene Testing ◽  
Mendelian Gene ◽  
Cornelia De Lange

ABSTRACTPurposeNeurodevelopmental phenotypes represent major indications for children undergoing clinical exome sequencing. However, 50% of cases remain undiagnosed even upon exome reanalysis. Here we show RNA sequencing (RNA-seq) on human B lymphoblastoid cell lines (LCL) is highly suitable for neurodevelopmental Mendelian gene testing and demonstrate the utility of this approach in suspected cases of Cornelia de Lange syndrome (CdLS).MethodsGenotype-Tissue Expression project transcriptome data for LCL, blood, and brain was assessed for neurodevelopmental Mendelian gene expression. Detection of abnormal splicing and pathogenic variants in these genes was performed with a novel RNA-seq diagnostic pipeline and using a validation CdLS-LCL cohort (n=10) and test cohort of patients who carry a clinical diagnosis of CdLS but negative genetic testing (n=5).ResultsLCLs share isoform diversity of brain tissue for a large subset of neurodevelopmental genes and express 1.8-fold more of these genes compared to blood (LCL, n=1706; whole blood, n=917). This enables testing of over 1000 genetic syndromes. The RNA-seq pipeline had 90% sensitivity for detecting pathogenic events and revealed novel diagnoses such as abnormal splice products in NIPBL and pathogenic coding variants in BRD4 and ANKRD11.ConclusionThe LCL transcriptome enables robust frontline and/or reflexive diagnostic testing for neurodevelopmental disorders.

scholarly journals The effect of Nipped-B-Like (Nipbl) haploinsufficiency on genome-wide cohesin binding and target gene expression: modeling Cornelia de Lange Syndrome

2017 ◽  
Author(s):  
Daniel A. Newkirk ◽  
Yen-Yun Chen ◽  
Richard Chien ◽  
Weihua Zeng ◽  
Jacob Biesinger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sister Chromatid ◽  
Target Genes ◽  
Sister Chromatid Cohesion ◽  
Ctcf Binding ◽  
Cornelia De Lange Syndrome ◽  
Specific Expression ◽  
Genome Wide ◽  
Chromatid Cohesion ◽  
Cornelia De Lange

ABSTRACTCornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl +/- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Thus, decreased cohesin binding at the gene regions directly contributes to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.

scholarly journals Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach

2019 ◽  
Vol 57 (5) ◽  
pp. 289-295 ◽  
Author(s):  
Patrizia Sarogni ◽  
Maria M Pallotta ◽  
Antonio Musio
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Therapeutic Approach ◽  
Genetic Disorder ◽  
Cornelia De Lange Syndrome ◽  
Biological Processes ◽  
Therapeutic Approaches ◽  
Chromatid Cohesion ◽  
Cornelia De Lange ◽  
State Of Art

Cornelia de Lange syndrome (CdLS) is a severe genetic disorder characterised by multisystemic malformations. CdLS is due to pathogenetic variants in NIPBL, SMC1A, SMC3, RAD21 and HDAC8 genes which belong to the cohesin pathway. Cohesin plays a pivotal role in chromatid cohesion, gene expression, and DNA repair. In this review, we will discuss how perturbations in those biological processes contribute to CdLS phenotype and will emphasise the state-of-art of CdLS therapeutic approaches.

scholarly journals Cornelia de Lange syndrome in children

2016 ◽  
pp. 102-107
Author(s):  
T. E. Bubnevich
Keyword(s):  
Mental Retardation ◽  
Upper Limb ◽  
Growth Retardation ◽  
Postnatal Growth ◽  
Cornelia De Lange Syndrome ◽  
Facial Dysmorphism ◽  
Malformation Syndrome ◽  
Postnatal Growth Retardation ◽  
Live Births ◽  
Cornelia De Lange

Cornelia de Lange syndrome is a multisystem malformation syndrome recognized primarily on the basis of characteristic facial dysmorphism, including low anterior hairline, arched eyebrows, synophrys, anteverted nares, maxillary prognathism, thin lips, «carp» mouth, in association with prenatal and postnatal growth retardation, mental retardation and, in many cases, upper limb anomalies. However, there are clinical options with milder phenotypes in this syndrome. The prevalence of the syndrome is 1:10,000-30,000 live births, occurs equally, regardless of gender. Although this syndrome is considered rare, experts agree that it is likely underdiagnosed.

Sign in / Sign up

Export Citation Format

Share Document