Prevalence of Immunological Defects in a Cohort of 97 Rubinstein–Taybi Syndrome Patients

Saettini, Francesco; Herriot, Richard; Prada, Elisabetta; Nizon, Mathilde; Zama, Daniele; Antonio, Miguel; Romaniouk, Igor; Lougaris, Vassilios; Cortesi, Manuela; Morreale, Alessia; Kosaki, Rika; Cardinale, Fabio; Ricci, Silvia; Domínguez‐Garrido, Elena; Montin, Davide; Vincent, Marie; Milani, Donatella; Biondi, Andrea; Gervasini, Cristina; Badolato, Raffaele

doi:10.1007/s10875-020-00808-4

Cited by 25 publications

(21 citation statements)

References 38 publications

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“…Saettini et al have reported on, a cohort of 97 RSTS patients, 72.1% of recurrent or severe infections, 12.3% of autoimmune/autoinflammatory complications, and 8.2% of lymphoproliferation. Syndromic immunodeficiency was diagnosed in 46.4% of patients [ 74 ].…”

Section: Clinical Descriptionmentioning

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: Clinical Descriptionmentioning

confidence: 99%

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Van-Gils

Magdinier

Fergelot

et al. 2021

Genes

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“…In KS1, this includes combined variable immunodeficiency with low IgA, as well as abnormal cell maturation 8,18,19 . In RT1, it includes hypogammaglobulinemia with a reduction of mature B cells 20 , while in KS2 the immune phenotype has been less extensively studied, with some evidence of mild hypogammaglobulinemia 18,21 . Given this potential overlap, we chose to profile positively selected B cells (CD19+; Methods ) from the peripheral blood of mutant mice, and that of age- and sex-matched wild-type littermates ( Figure 1d ).…”

Section: Resultsmentioning

confidence: 99%

“…We then reasoned that we might gain more insight by focusing on two of the specific phenotypes seen in KS1: abnormal B-cell maturation, and IgA deficiency 13,20 . We set out to test if these are attributable to the collective dysregulation of multiple genes, or to the abnormal expression of a select few.…”

Section: The Collective Effect Of Individually Subtle Aberrations In mentioning

confidence: 99%

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

Luperchio

Boukas

Zhang

et al. 2020

Preprint

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The Mendelian Disorders of the Epigenetic Machinery (MDEMs) have emerged as a class of Mendelian disorders caused by loss-of-function variants in epigenetic regulators. Although each MDEM has a different causative gene, they exhibit several overlapping disease manifestations. Here, we hypothesize that this phenotypic convergence is a consequence of common abnormalities at the epigenomic level, which directly or indirectly lead to downstream convergence at the transcriptomic level. This implies that identifying abnormalities shared across multiple MDEMs could pinpoint locations where epigenetic variation is causally related to disease phenotypes. To test our hypothesis, we perform a comprehensive interrogation of chromatin (ATAC-Seq) and expression (RNA-Seq) states in B cells from mouse models of three MDEMs (Kabuki types 1&2 and Rubinstein-Taybi syndromes). We build on recent work in covariate-powered multiple testing to develop a new approach for the overlap analysis, which enables us to find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often leads to disruption of downstream gene expression, and identify a total of 463 loci and 249 genes commonly disrupted across the three MDEMs. As an example of how widespread dysregulation leads to specific phenotypes, we show that subtle expression alterations of multiple, directly relevant genes, collectively contribute to IgA deficiency in KS1 and RT. In contrast, we predict that KS2 does not have IgA deficiency, and confirm this pattern in mice. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

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“…Although the trio-WES analysis makes a dual molecular diagnosis extremely unlikely, the presence of distinct immunological features in the two patients does not exclude the presence of deep intronic variants or the influence of not-yet-known genes. A significant proportion of patients with RSTS suffers from immunodeficiency, autoimmune, and autoinflammatory conditions, but the reason for the switch from typical RSTS to syndromic PID is not known (Saettini et al, 2020) Met1588Thr mutation both at aminoacidic and domain level, above and below the figures, respectively. In order (from N terminus to C-terminus), p300 protein domains are as follows: zf-TAZ, TAZ zinc finger; KIX, CREB interaction; Bromo, bromodomain; Ring, ring domain; PHD, plant homeodomain; KAT, lysine acetyltransferase; COaBS, CoA-binding site; ZZ_CBP, zinc finger; ZnF_TAZ, TAZ zinc finger; CREBB, Creb_binding.…”

Section: Clinical and Discussionmentioning

confidence: 99%

Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

Saettini

Fazio

Bonati

et al. 2022

American J of Med Genetics Pt A

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The Rubinstein–Taybi syndrome (RSTS) is a rare developmental disorder characterized by craniofacial dysmorphisms, broad thumbs and toes, intellectual disability, growth deficiency, and recurrent infections. Mutations in the cyclic adenosine monophosphate response element‐binding protein (CREB)‐binding protein (CREBBP) or in the E1A‐associated protein p300 (EP300) genes have been demonstrated in 55% (RSTS1) and up to 8% of the patients (RSTS2), respectively. Dysfunction of immune response has been reported in a subgroup of individuals with RSTS. Here we characterize two patients carrying the same EP300 variant and distinctive RSTS features (including congenital heart abnormalities, short stature, feeding problems, and gastroesophageal reflux). Whole exome sequencing did not support a dual molecular diagnosis hypothesis. Nonetheless, patients showed distinct clinical manifestations and immunological features. The most severe phenotype was associated with reduced T‐cell production and diversity. This latter feature was confirmed in a control group of four RSTS patients.

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Prevalence of Immunological Defects in a Cohort of 97 Rubinstein–Taybi Syndrome Patients

Cited by 25 publications

References 38 publications

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

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