Case report: a typical Silver-Russell syndrome patient with hand dystonia: the valuable support of the consensus statement to the wide syndromic spectrum

The amount of Insulin Growth Factor 2 (IGF2) controls the rate of embryonal and postnatal growth. The IGF2 and adjacent H19 are the imprinted genes of the telomeric cluster in the 11p15 chromosomal region regulated by differentially methylated regions (DMRs) or imprinting centers (ICs): H19/IGF2:IG-DMR (IC1). Dysregulation due to IC1 Loss-of-Methylation (LoM) or Gain-of-Methyaltion (GoM) causes Silver–Russell syndrome (SRS) or Beckwith–Wiedemann syndrome (BWS) disorders associated with growth retardation or overgrowth, respectively. Specific features define each of the two syndromes, but isolated asymmetry is a common cardinal feature, which is considered sufficient for a diagnosis in the BWS spectrum. Here, we report the case of a girl with right body asymmetry, which suggested BWS spectrum. Later, BWS/SRS molecular analysis identified IC1_LoM revealing the discrepant diagnosis of SRS. A clinical re-evaluation identified a relative macrocephaly and previously unidentified growth rate at lower limits of normal at birth, feeding difficulties, and asymmetry. Interestingly, and never previously described in IC1_LoM SRS patients, since the age of 16, she has developed hand-writer’s cramps, depression, and bipolar disorder. Trio-WES identified a VPS16 heterozygous variant [NM_022575.4:c.2185C>G:p.Leu729Val] inherited from her healthy mother. VPS16 is involved in the endolysosomal system, and its dysregulation is linked to autosomal dominant dystonia with incomplete penetrance and variable expressivity. IGF2 involvement in the lysosomal pathway led us to speculate that the neurological phenotype of the proband might be triggered by the concurrent IGF2 deficit and VPS16 alteration

Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients

BACKGROUND: Rubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBP or CBP) in 16p13.3. To date mutations in CREBBP have been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions. METHODS: Our study is based on the mutation analysis of CREBBP in 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments. RESULTS: We identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1–170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected. CONCLUSION: A high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far

An Integrated IT System for Phenotypic and Genotypic Data Mining and Management

This paper describes the application of an information technology infrastructure aimed at supporting translational bioinformatics studies which need the joint management of phenotypic and genotypic data. The system provides an integrated and easy to use software environment, based on data warehouse and data mining tools, to discover the most frequent complex phenotypes and search their penetrance and heritability by mapping them on the population pedigree. We first use a logical formalization to define phenotypes of interest in order to retrieve individuals having that phenotype from the electronic medical record. We then use an open-source Web-based data warehouse application for analyzing phenotypic data and presenting the results in a multidimensional format. Relationships between the selected individuals are automatically visualized by integrating in the system an ad-hoc developed pedigree visualization tool. Finally, the application of the system to support a genetic study of an isolated population, the Val Borbera project, is presented

Automatic pedigree reconstruction for genetic studies in isolated populations

This paper describes a tool implemented to automatically reconstruct the pedigree of an isolated population of Northern Italy with the aim of supporting genetic studies. The goal of such studies is to analyze genealogic, clinical and genetic data for genetic dissection of complex diseases. In this context the reconstruction of the population pedigree is fundamental to verify that such population is a genetic isolate and obtain the parental relationships among the individuals participating to the study. The algorithm presented in the paper, from heterogeneous data sources (demographic municipal and parish archives and other data sources), derives the pedigree applying several heuristic rules in a predefined order One of the main difficulties in performing such task stands in the "record linkage" process that requires the definition of a sufficiently general strategy for managing the ambiguities caused by missing or imprecise/erroneous input data. The paper, finally, presents and discusses the preliminary results obtained by reconstructing the pedigree of four villages from the data collected during the first eighteen months of project

Translational Bioinformatics: Challenges and Opportunities forCase-Based Reasoning and Decision Support

Translational bioinformatics is bioinformatics applied to human health. Although, up to now, its main focus has been to support molecular medicine research, translational bioinformatics has now the opportunity to design clinical decision support systems based on the combination of -omics data and internet-based knowledge resources. The paper describes the state-of-art of translational bioinformatics highlighting challenges and opportunities for decision support tools and case-based reasoning. It finally reports the design of a new system for supporting diagnosis in dilated cardiomyopathy. The system is able to combine text mining, literature search and case-based retrieval

Histone acetylation deficits in lymphoblastoid cell lines from patients with rubinstein-Taybi syndrome

Background: Rubinstein-Taybi syndrome (RSTS) is a congenital neurodevelopmental disorder defined by postnatal growth deficiency, characteristic skeletal abnormalities and mental retardation and caused by mutations in the genes encoding for the transcriptional co-activators with intrinsic lysine acetyltransferase (KAT) activity CBP and p300. Previous studies have shown that neuronal histone acetylation is reduced in mouse models of RSTS. Methods: The authors identified different mutations at the CREBBP locus and generated lymphoblastoid cell lines derived from nine patients with RSTS carrying distinct CREBBP mutations that illustrate different grades of the clinical severity in the spectrum of the syndrome. They next assessed whether histone acetylation levels were altered in these cell lines. Results: The comparison of CREBBP-mutated RSTS cell lines with cell lines derived from patients with an unrelated mental retardation syndrome or healthy controls revealed significant deficits in histone acetylation, affecting primarily histone H2B and histone H2A. The most severe defects were observed in the lines carrying the whole deletion of the CREBBP gene and the truncating mutation, both leading to a haploinsufficiency state. Interestingly, this deficit was rescued by treatment with an inhibitor of histone deacetylases (HDACi). Conclusions: The authors' results extend to humans the seminal observations in RSTS mouse models and point to histone acetylation defects, mainly involving H2B and H2A, as relevant molecular markers of the disease.This study was supported by the ItalyeSpain bilateral MIUR project (referred to as IT08143C4F in Italy and HI2007-0203 in Spain). Research at Larizza’s lab is supported by a grant from ASM (Associazione Studio Malformazioni). Research at Barco’s lab is supported by the grants from the Spanish Ministry of Science and Innovation BFU2008-00611, CSD2007-00023 and SAF2008-03194-E (part of the coordinated ERA-Net NEURON project Epitherapy) and a grant from Fundación Ramón Areces. JLA has a Juan de la Cierva contract given by the Spanish Ministry of Science and Innovation.Peer Reviewe

Rings and Bricks: Expression of Cohesin Components is Dynamic during Development and Adult Life.

Cohesin complex components exert fundamental roles in animal cells, both canonical in cell cycle and non-canonical in gene expression regulation. Germline mutations in genes coding for cohesins result in developmental disorders named cohesinopaties, of which Cornelia de Lange syndrome (CdLS) is the best-known entity. However, a basic description of mammalian expression pattern of cohesins in a physiologic condition is still needed. Hence, we report a detailed analysis of expression in murine and human tissues of cohesin genes defective in CdLS. Using both quantitative and qualitative methods in fetal and adult tissues, cohesin genes were found to be ubiquitously and differentially expressed in human tissues. In particular, abundant expression was observed in hematopoietic and central nervous system organs. Findings of the present study indicate tissues which should be particularly sensitive to mutations, germline and/or somatic, in cohesin genes. Hence, this expression analysis in physiological conditions may represent a first core reference for cohesinopathies.This work has been supported by Fondazione Cariplo, grant No. 2015-0783 to Valentina Massa, and by Fondazione Mariani (Como, Italy) to Angelo Selicorni