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J Dermatol 2021 Jun 12. Epub 2021 Jun 12.

Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.

Neural Regen Res 2022 Jan;17(1):5-14

Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano, Milano, Italy.

Taking advantage of the fast-growing knowledge of RNA-binding proteins (RBPs) we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons (iNeurons) modelling the neurodevelopmental Rubinstein Taybi Syndrome (RSTS) caused by mutations in the genes encoding CBP/p300 acetyltransferases. We discuss top and functionally connected downregulated genes sorted to "RNA processing" and "Ribonucleoprotein complex biogenesis" Gene Ontology clusters. The first set of downregulated RBPs includes members of hnRNHP (A1, A2B1, D, G, H2-H1, MAGOHB, PAPBC), core subunits of U small nuclear ribonucleoproteins and Serine-Arginine splicing regulators families, acting in precursor messenger RNA alternative splicing and processing. Read More

Int J Mol Sci 2021 May 28;22(11). Epub 2021 May 28.

Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy.

Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in or genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 -mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients' iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0. Read More

Pediatr Hematol Oncol 2021 May 21:1-6. Epub 2021 May 21.

Pediatric Hematology Department, Fondazione MBBM, Universita degli Studi di Milano-Bicocca Dipartimento di Medicina e Chirurgia, Monza, Italy.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by variants in or . Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, intellectual disability and immunodeficiency. Here we report on one RSTS patient who experienced hemophagocytic lymphohystiocytosis (HLH) and disseminated herpes virus 1 ( HSV-1) disease. Read More

Eur Rev Med Pharmacol Sci 2021 Apr;25(7):2949-2957

Unit of Medical Genetics, "Madonna delle Grazie" Hospital, Matera, Italy.

Objective: Array-CGH is a powerful tool in identifying and characterizing complex genomic rearrangements smaller than 5-10 megabase (Mb), for which classical cytogenetic approaches are not sensitive enough. The use of Array-CGH has increased of 10-20% the detection rate of unbalanced cryptic rearrangements, such as deletions and/or duplications.

Patients And Methods: We present here the first report of a patient with 7q35q36. Read More

Int J Mol Sci 2021 Mar 31;22(7). Epub 2021 Mar 31.

Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy.

The short-chain fatty acid butyrate, produced by the gut microbiota, acts as a potent histone deacetylase (HDAC) inhibitor. We assessed possible ameliorative effects of butyrate, relative to other HDAC inhibitors, in in vitro and in vivo models of Rubinstein-Taybi syndrome (RSTS), a severe neurodevelopmental disorder caused by variants in the genes encoding the histone acetyltransferases CBP and p300. In RSTS cell lines, butyrate led to the patient-specific rescue of acetylation defects at subtoxic concentrations. Read More

Mol Syndromol 2021 Mar 30;12(1):52-56. Epub 2020 Nov 30.

Department of Medical Genetics, Faculty of Medicine, Ataturk University, Erzurum, Turkey.

Floating-Harbor syndrome (FHS) is a rare autosomal dominant genetic disorder characterized by proportionate short stature with delayed bone maturation, lack of expressive language, and distinctive facial features including a large nose, long eyelashes, deeply set eyes, and triangular face. Mutations in the gene cause truncated SNF2-related CREBBP activator protein (SRCAP) and lead to FHS. SRCAP is one of several proteins that act as coactivator for the CREB-binding protein which is associated with Rubinstein-Taybi syndrome (RSTS). Read More

Front Genet 2021 4;12:640992. Epub 2021 Mar 4.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Familial Rubinstein-Taybi syndrome (RSTS) with recurrent RSTS siblings and apparently unaffected parents is rare; such cases might result from parental somatic and/or germline mosaicism. Parental low-level (<10%) germline mosaicism in the CREBBP-associated RSTS family has not been reported. Here, we present our studies of a Chinese family with two RSTS siblings and apparently unaffected parents. Read More

Eur Rev Med Pharmacol Sci 2021 Feb;25(3):1447-1454

Department of Neonatology, Hunan Provincial People's Hospital/First Affiliated Hospital of Hunan Normal University, Changsha, China.

The aim of this study was to analyze the clinical features of a Rubinstein-Taybi syndrome (RSTS) case with neonatal glaucoma. We also wanted to explore the manifestation of the disease in combination with genotype-phenotype correlation. For DNA extraction we used 2 ml peripheral blood, collected from the child and parents. Read More

Mol Biol Rep 2021 Mar 24;48(3):2117-2122. Epub 2021 Feb 24.

Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Preeclampsia (PE) is a major complication of pregnancy and remains a leading cause of neonatal and maternal mortality worldwide. Several studies have revealed that the incidence of preeclampsia is high in mothers who carried a fetus with Rubinstein-Taybi Syndrome due to the mutation in CREBBP. We aimed to compare the expression level of the CERBBP gene between preeclamptic and healthy placenta in our study. Read More

J Med Genet 2021 Jan 18. Epub 2021 Jan 18.

Texas Children's Hospital, Houston, Texas, USA

Background: Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.

Methods: We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions. Read More

Am J Med Genet A 2021 04 14;185(4):1251-1255. Epub 2021 Jan 14.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant genetic syndrome characterized by distinct facial features, broad thumbs, growth restriction, microcephaly, intellectual disability, and developmental delay. Pathogenic variants in both CREBBP and EP300 have been associated with RSTS. Here we present a case of a female with hyperinsulinism and features consistent with RSTS, found to have a pathogenic variant in EP300. Read More

Protein J 2021 02 4;40(1):19-27. Epub 2021 Jan 4.

Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

CBP [cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein] is one of the most researched proteins for its therapeutic function. Several studies have identified its vast functions and interactions with other transcription factors to initiate cellular signals of survival. In cancer and other diseases such as Alzheimer's, Rubinstein-taybi syndrome, and inflammatory diseases, CBP has been implicated and hence an attractive target in drug design and development. Read More

Cureus 2020 Nov 25;12(11):e11709. Epub 2020 Nov 25.

Gastroenterology, Cleveland Clinic, Cleveland, USA.

Rubinstein-Taybi syndrome (RSTS; Online Mendelian Inheritance in Man [OMIM] #180849, #613684; Orpha: 783 ) is a rare plurimalformative autosomal dominant genetic disorder that affects one in 100,000-125,000 newborns with equal male and female distribution. It is characterized by distinctive facial features, short stature, broad and often angulated thumbs and halluces, and moderate-to-severe intellectual disability. In addition to ocular, cardiac, renal, endocrinologic, neurological, and psychomotor abnormalities, RSTS individuals can present with several gastrointestinal symptoms such as feeding difficulties, gastroesophageal reflux, and constipation. Read More

J Comput Neurosci 2021 02 11;49(1):37-56. Epub 2020 Nov 11.

Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

Genetic disorders such as Rubinstein-Taybi syndrome (RTS) and Coffin-Lowry syndrome (CLS) cause lifelong cognitive disability, including deficits in learning and memory. Can pharmacological therapies be suggested that improve learning and memory in these disorders? To address this question, we simulated drug effects within a computational model describing induction of late long-term potentiation (L-LTP). Biochemical pathways impaired in these and other disorders converge on a common target, histone acetylation by acetyltransferases such as CREB binding protein (CBP), which facilitates gene induction necessary for L-LTP. Read More

Am J Med Genet A 2021 01 16;185(1):267-273. Epub 2020 Oct 16.

Clinical Genetic Service, Department of Health, Kowloon, Hong Kong.

Rubinstein-Taybi syndrome (RSTS, OMIM*180849) is a rare autosomal dominant disorder, characterized by distinctive facial features, short stature, broad and often angulated thumbs and halluces, with occasional congenital anomalies. Characteristic facial dysmorphic features include downslanting palpebral fissures, low hanging columella. RSTS is caused by pathogenic variants in two ubiquitously expressed and highly homologous genes, CREBBP (OMIM*600140) and EP300 (OMIM*600140). Read More

Am J Med Genet A 2021 01 16;185(1):105-111. Epub 2020 Oct 16.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia.

The journey to receiving a diagnosis for rare genetic disease can be long and emotionally impactful. This study describes parental experiences of receiving their child's diagnosis of Rubinstein-Taybi syndrome (RTS), a rare genetic condition characterized by growth and developmental delay together with dysmorphic features. Parents from the RTS Australia support group participated in qualitative, semi-structured phone interviews, which were transcribed verbatim and thematically analyzed. Read More

Am J Med Genet A 2020 12 11;182(12):2926-2938. Epub 2020 Oct 11.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Pathogenic variants in the homologous and highly conserved genes-CREBBP and EP300-are causal for Rubinstein-Taybi syndrome (RSTS). CREBBP and EP300 encode histone acetyltransferases (HAT) that act as transcriptional co-activators, and their haploinsufficiency causes the pathology characteristic of RSTS by interfering with global transcriptional regulation. Though generally a well-characterized syndrome, there is a clear phenotypic spectrum; rare associations have emerged with increasing diagnosis that is critical for comprehensive understanding of this rare syndrome. Read More

Brain Res 2020 12 3;1749:147140. Epub 2020 Oct 3.

Cluster for Pioneering Research, RIKEN, Tsukuba, Ibaraki 305-0074, Japan.

Neurodevelopmental disorders, including intellectual disability and autism spectrum disorder, are often caused by de novo autosomal dominant mutations. While mouse models are frequently used to investigate these disorders, the genetic background sometimes affects the appearance or severity of mutant phenotypes. In a previous report, we developed a system to produce de novo heterozygous mutant mice using the Cre-LoxP system without the need to maintain the heterozygous mutant line itself (Takagi et al. Read More

Am J Med Genet A 2020 12 27;182(12):2939-2950. Epub 2020 Sep 27.

Kapi'olani Medical Center and University of Hawai'i, Honolulu, Hawaii, USA.

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. Read More

J Nippon Med Sch 2020 Aug 31. Epub 2020 Aug 31.

Department of Gastrointestinal Surgery and Surgical Oncology, Ehime University Graduate School of Medicine.

Rubinstein-Taybi syndrome is an extremely rare autosomal dominant genetic disorder that occurs in 1/125,000 and is characterized by distinctive facial appearance, short stature, mild to severe mental retardation, and higher risk for cancer. In addition, variable organ anomalies had been reported. Paraovarian cyst causing torsion of the ipsilateral fallopian tube is less common, with an estimated incidence of 1/1,500,000, but it can adversely affect tubal function. Read More

Front Cell Dev Biol 2020 4;8:710. Epub 2020 Aug 4.

Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders called Mendelian Disorders of the Epigenetic Machinery (MDEM). This study aims to determine the prevalence of olfactory malformations in a heterogeneous group of subjects with MDEM. Read More

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

BC Children's Hospital Research Institute, Vancouver, British Columbia V5Z 4H4, Canada.

Within histone H3, lysine 27 (H3K27) is one of the residues that functions as a molecular switch, by virtue of being subject to mutually exclusive post-translational modifications that have reciprocal effects on gene expression. Whereas acetylation of H3K27 is associated with transcriptional activation, methylation at this residue causes transcriptional silencing; these two modifications are mutually exclusive. Establishment of these epigenetic marks is important in defining cellular identity and for maintaining normal cell function, as evidenced by rare genetic disorders of epigenetic writers involved in H3K27 post-translational modification. Read More

J Mol Neurosci 2021 Mar 25;71(3):607-612. Epub 2020 Aug 25.

Dongguan Maternal and Child Health Care Hospital, Dongguan, 523120, China.

Loss-of-function variants in CREBBP or EP300 result in Rubinstein-Taybi syndrome (RSTS). The previously reported cluster of variants in the last part of exon 30 and the beginning of exon 31 of CREBBP, overlapping with the ZNF2 (zinc finger, ZZ-type; residues 1701 to 1744) and ZNF3 (zinc finger, TAZ-type; residues 1764 to 1853) domains, is associated with atypical RSTS. The main features include developmental delay, short stature, microcephaly, distinctive facial features, autistic behavior, feeding difficulties, recurrent upper airway infections, and hearing impairment. Read More

Am J Med Genet A 2020 11 21;182(11):2508-2520. Epub 2020 Aug 21.

Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.

Pathogenic variants within the CREBBP and EP300 genes account for the majority of individuals with Rubinstein-Taybi syndrome (RSTS). Data are presented from a large cohort of 395 individuals referred for diagnostic testing of CREBBP, and of the 19 CREBBP missense variants classified as likely pathogenic in this study, 17 were within the histone acetyltransferase (HAT) domain, providing evidence that this domain is critical to the normal function of the CREBBP protein (CBP). The data presented here, combined with other published results, suggest that the presence of a missense variant within the CBP HAT domain can be considered as moderate evidence of pathogenicity in the context of official variant interpretation guidelines. Read More

An Bras Dermatol 2020 Sep - Oct;95(5):619-622. Epub 2020 Jul 15.

Dermatology Service, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil; Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil; Pediatric Dermatology Unit, Dermatology Service, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address:

Pilomatricomas are benign tumors originating from the capillary matrix, which may present as solitary lesions or, less commonly, multiple. Myotonic dystrophy and familial adenomatous polyposis are the most frequently associated disorders with multiple pilomatricomas. There are few reports relating these tumors to other genetic syndromes. Read More

Eur J Hum Genet 2021 Jan 8;29(1):88-98. Epub 2020 Jul 8.

Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as "writer" of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann-Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Read More

J Clin Immunol 2020 08 27;40(6):851-860. Epub 2020 Jun 27.

Departamento de Nefrología, Hospital Universitario de Santiago, Santiago de Compostela, Spain.

Although recurrent infections in Rubinstein-Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. Read More

Mol Neurobiol 2020 Sep 20;57(9):3685-3701. Epub 2020 Jun 20.

Cytogenetics and Molecular Genetics Laboratory, Istituto Auxologico Italiano, IRCCS, Milan, Italy.

Rubinstein-Taybi syndrome (RSTS) is a rare multisystem developmental disorder with moderate to severe intellectual disability caused by heterozygous mutations of either CREBBP or EP300 genes encoding CBP/p300 chromatin regulators. We explored the gene programs and processes underlying the morphological and functional alterations shown by iPSC-derived neurons modeling RSTS to bridge the molecular changes resulting from defective CBP/p300 to cognitive impairment. By global transcriptome analysis, we compared the differentially expressed genes (DEGs) marking the transition from iPSC-derived neural progenitors to cortical neurons (iNeurons) of five RSTS patients carrying private CREBBP/EP300 mutations and manifesting differently graded neurocognitive signs with those of four healthy controls. Read More

J Ultrasound 2020 Jun 18. Epub 2020 Jun 18.

Department of Obstetrics and Gynecology "L. Mangiagalli", Fondazione IRCCS "Ca' Granda"- Ospedale Maggiore Policlinico, Milan, Italy.

Rubinstein-Taybi syndrome is a rare genetic multisystem disorder with an estimated prevalence between 1 per 100,000-125,000 live births. Diagnosis is usually clinical and subsequent to birth. In fact, the rarity of the syndrome and the presence of aspecific morphologic anomalies make prenatal diagnosis challenging. Read More