Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

Shangguan, Huakun; Chen, Ruimin

doi:10.3389/fped.2022.940294

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…Alternatively, BRD4 may have unique enhancer regulatory roles independent of NIPBL and cohesin during craniofacial development. Aside from cohesin subunits and BRD4, several enhancer regulatory factors can also be mutated in CdLS including the EP300 histone acetylase (Cucco et al 2020;Woods et al 2014), MED13L of the mediator complex (Aoi et al 2019), as well as KDM6A and KMT2D histone modifiers (Shangguan and Chen 2022) that function at enhancers and regulate cNCC osteoblast differentiation (Shpargel et al , 2020Wang et al 2016;Shpargel and Quickstad 2023).…”

Section: Development • Accepted Manuscriptmentioning

confidence: 99%

BRD4 binds to active cranial neural crest enhancers to regulate RUNX2 activity during osteoblast differentiation

Musa,

Lester,

Quickstad

et al. 2024

Development

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Cornelia de Lange syndrome (CdLS) is a congenital disorder featuring facial dysmorphism, postnatal growth deficits, cognitive disability, and upper limb abnormalities. CdLS is genetically heterogeneous with cases arising from mutation of BRD4, a bromodomain protein that binds and reads acetylated histones. In this study we have modeled CdLS facial pathology through mouse neural crest cell (NCC) specific mutation of BRD4 to characterize cellular and molecular function in craniofacial development. Mice with BRD4 NCC loss of function died at birth with severe facial hypoplasia, cleft palate, mid-facial clefting, and exencephaly. Following migration, BRD4 mutant NCCs initiated RUNX2 expression for differentiation to osteoblast lineages but failed to induce downstream RUNX2 targets required for lineage commitment. BRD4 bound to active enhancers to regulate expression of osteogenic transcription factors and extracellular matrix components integral for bone formation. RUNX2 physically interacts with a carboxy-terminal (C-terminal) domain in the long isoform of BRD4, can co-occupy osteogenic enhancers, and this association is required for RUNX2 recruitment and appropriate osteoblast differentiation. We conclude that BRD4 controls facial bone development through osteoblast enhancer regulation of the RUNX2 transcriptional program.

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Section: Development • Accepted Manuscriptmentioning

confidence: 99%

BRD4 binds to active cranial neural crest enhancers to regulate RUNX2 activity during osteoblast differentiation

Musa,

Lester,

Quickstad

et al. 2024

Development

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“…BRD4 and ANKRD11 have recently been added to a list of genes causing CdLS [51]. BRD4 encodes chromatin-associated proteins which cooperate with NIPBL in transcriptional regulation.…”

Section: Cohesin Complexmentioning

confidence: 99%

“…Constipation and GERD are more common in patients with variants in the NIPBL and SMC1A genes, visual impairment in NIPBL, SMC1A, and HDAC8, structural brain abnormalities in NIPBL, and sleep problems in NIPBL and SMC1A [56,66]. Dysmorphic features that meet the clinical diagnostic criteria for CdLS can also be seen in people with changes in the BRD4, RAD21, or ANKRD11 genes, although they are not as severe or common [7,51]. Comprehensive molecular analysis in a cohort of 716 probands with CdLS revealed that causative variants in genes such as AFF4, ANKRD11, ARCN1, ARID1B, ASXL2, and others account for a significant proportion of etiologies beyond the traditional CdLS genes (25% of probands) [7].…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

Advancing the Clinical and Molecular Understanding of Cornelia de Lange Syndrome: A Multidisciplinary Pediatric Case Series and Review of the Literature

Gruca-Stryjak,

Doda-Nowak,

Dzierla

et al. 2024

JCM

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Cornelia de Lange syndrome (CdLS) is a complex genetic disorder with distinct facial features, growth limitations, and limb anomalies. Its broad clinical spectrum presents significant challenges in pediatric diagnosis and management. Due to cohesin complex mutations, the disorder’s variable presentation requires extensive research to refine care and improve outcomes. This article provides a case series review of pediatric CdLS patients alongside a comprehensive literature review, exploring clinical variability and the relationship between genotypic changes and phenotypic outcomes. It also discusses the evolution of diagnostic and therapeutic techniques, emphasizing innovations in genetic testing, including detecting mosaicism and novel genetic variations. The aim is to synthesize case studies with current research to advance our understanding of CdLS and the effectiveness of management strategies in pediatric healthcare. This work highlights the need for an integrated, evidence-based approach to diagnosis and treatment. It aims to fill existing research gaps and advocate for holistic care protocols and tailored treatment plans for CdLS patients, ultimately improving their quality of life.

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Clinical Characteristics, Genetic Analysis, and Literature Review of Cornelia de Lange Syndrome Type 4 Associated With a RAD21 Variant

Yue,

Chen,

et al. 2024

Molec Gen & Gen Med

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BackgroundCornelia de Lange syndrome (CdLS) is an uncommon congenital developmental disorder distinguished by intellectual disorder and distinctive facial characteristics, with a minority of cases attributed to RAD21 variants.MethodsA patient was admitted to the endocrinology department at Peking Union Medical College Hospital, where 2 mL of peripheral venous blood was collected from the patient and his parents. DNA was extracted for whole‐exome sequencing (WES) analysis, and the genetic variation of the parents was confirmed through Sanger sequencing.ResultsA 13.3‐year‐old male patient with a height of 136.5 cm (−3.5 SDS) and a weight of 28.4 kg (−3.1 SDS) was found to have typical craniofacial features. WES revealed a pathogenic variant c.1143G>A (p.Trp381*) in the RAD21 gene. He was diagnosed with CdLS type 4 (OMIM #614701). We reviewed 36 patients with CdLS related to RAD21 gene variants reported worldwide from May 2012 to March 2024. Patient's variant status, clinical characteristics, and rhGH treatment response were summarized. Frameshift variants constituted the predominant variant type, representing 36% (13/36) of cases. Clinical features included verbal developmental delay and intellectual disorder observed in 94% of patients.ConclusionThis study reported the third case of CdLS type 4 in China caused by a RAD21 gene variant, enriching the genetic mutational spectrum.

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Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

Cited by 6 publications

References 33 publications

BRD4 binds to active cranial neural crest enhancers to regulate RUNX2 activity during osteoblast differentiation

BRD4 binds to active cranial neural crest enhancers to regulate RUNX2 activity during osteoblast differentiation

Advancing the Clinical and Molecular Understanding of Cornelia de Lange Syndrome: A Multidisciplinary Pediatric Case Series and Review of the Literature

Clinical Characteristics, Genetic Analysis, and Literature Review of Cornelia de Lange Syndrome Type 4 Associated With a RAD21 Variant

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