Pathogenic variants in <scp><i>EP300</i></scp> and <scp><i>ANKRD11</i></scp> in patients with phenotypes overlapping Cornelia de Lange syndrome

Cucco, Francesco; Sarogni, Patrizia; Rossato, Sara; Alpa, Mirella; Patimo, Alessandra; Latorre, Ana; Magnani, Cinzia; Puisac, Beatriz; Ramos, Feliciano J.; Pié, Juan; Musio, Antonio

doi:10.1002/ajmg.a.61611

Cited by 38 publications

(20 citation statements)

References 53 publications

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“…Woods et al and Cucco et al have identified EP300 mutation in two patients with an initial diagnosis of Cornelia de Lange syndrome (CdLS, OMIM #122470, #300590, #610759, #614701, #300882, #608749) [ 162 , 163 ]. To date, six genes were implicated in the CdLS ( NIPBL , SMC1A , SMC3 , RAD21 , HDAC8 , and BRD4 ) and all of them encode proteins linked to the Cohesin complex [ 164 , 165 ] involved in chromatin organization and transcriptional regulation.…”

Section: Epigenetic Regulation and Cognitive Function In Rstsmentioning

confidence: 99%

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Van-Gils

Magdinier

Fergelot

et al. 2021

Genes

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The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy.

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Section: Epigenetic Regulation and Cognitive Function In Rstsmentioning

confidence: 99%

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Van-Gils

Magdinier

Fergelot

et al. 2021

Genes

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“…Mutations in other genes have also been reported (reviewed in (Kline et al, 2018), Table 1): mutations in SMC1A have been identified in an estimated 5% of individuals with CdLS, usually associated to a non-classical phenotype (Musio et al, 2006;Borck et al, 2007;Deardorff et al, 2007;Ansari et al, 2014;Huisman et al, 2017); a SMC3 variant has been found in an individual with atypical CdLS (Deardorff et al, 2007) and others have been associated to individuals with some overlapping phenotypical features but not fulfilling the diagnostic criteria of non-classic CdLS (Ansari et al, 2014;Gil-Rodriguez et al, 2015); RAD21 variants have been found in a small percentage of non-classic CdLS cases ((Deardorff et al, 2012b) and reviewed in (Cheng et al, 2020)); HDAC8 variants have been also reported, with a typically heterogeneous non-classic phenotype, but also with some classic CdLS cases (Deardorff et al, 2012a;Harakalova et al, 2012;Ansari et al, 2014;Feng et al, 2014;Kaiser et al, 2014;Parenti et al, 2016;Helgeson et al, 2018;Jezela-Stanek et al, 2019); BRD4 mutations have been associated with few cases of non-classic CdLS (Olley et al, 2018;Alesi et al, 2019); and other gene variants have been identified, mainly by exome sequencing, associated with individuals with limited clinical CdLS features, like variants of EP300 (Woods et al, 2014;Cucco et al, 2020), AFF4 (Izumi et al, 2015), KMT2A (Yuan et al, 2015;Parenti et al, 2017;Aoi et al, 2019), NAA10 (Saunier et al, 2016), TAF6 (Yuan et al, 2015), ANKRD11 (Ansari et al, 2014;Parenti et al, 2016;…”

Section: Nipblmentioning

confidence: 99%

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

García-Gutiérrez

García-Domínguez

2021

Front. Mol. Biosci.

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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.

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“…However, the diagnosis may be hard to achieve in individuals with atypical presentations, either because of phenotypic overlap with clinically and molecularly related disorders such as Cornelia de Lange syndrome or Floating-Harbor syndrome (Cucco et al, 2020;Hood et al, 2016), or the subtle presentation of physical features in some cases. The phenotypic spectrum of RSTS has been elucidated through multiple case reports and large cohort studies.…”

Section: Introductionmentioning

confidence: 99%

Rubinstein–Taybi syndrome in diverse populations

Tekendo‐Ngongang

Owosela

Fleischer³

et al. 2020

American J of Med Genetics Pt A

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Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was

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Pathogenic variants in EP300 and ANKRD11 in patients with phenotypes overlapping Cornelia de Lange syndrome

Cited by 38 publications

References 53 publications

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

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

Rubinstein–Taybi syndrome in diverse populations

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