Cyclin-dependent kinase inhibitors (CDKIs) are known targets to become deregulated in various tumour types, including endocrine tumours. Typically, these cell cycle regulators are somatically ...inactivated in sporadic endocrine tumours. Recently, it became known that certain CDKI genes cause inherited susceptibility to endocrine neoplasia. Multiple endocrine neoplasia type 4 (MEN4) emerged as a novel form of multiple endocrine neoplasia, caused by mutations in the CDKI gene CDKN1B /p27Kip1 . The MEN4 phenotype remains unclear, but all MEN4 patients identified thus far present with parathyroid involvement, and less typically with pituitary adenomas and other endocrine features. Moreover, the CDKI gene CDKN2C /p18INK4C has been also implicated in endocrine neoplasia susceptibility. This review presents the recent advances in these novel MEN-related states and summarises the current knowledge of how these CDKIs may be implicated in endocrine neoplasia. In addition, it briefly presents data from Cdkn1b /p27Kip1 and Cdkn2c /p18INK4C murine models, which strongly support the protective role of these inhibitors against endocrine tumourigenesis.
The increasing volume and complexity of high-throughput genomic data make analysis and prioritization of variants difficult for researchers with limited bioinformatics skills. Variant Ranker allows ...researchers to rank identified variants and determine the most confident variants for experimental validation.
We describe Variant Ranker, a user-friendly simple web-based tool for ranking, filtering and annotation of coding and non-coding variants. Variant Ranker facilitates the identification of causal variants based on novelty, effect and annotation information. The algorithm implements and aggregates multiple prediction algorithm scores, conservation scores, allelic frequencies, clinical information and additional open-source annotations using accessible databases via ANNOVAR. The available information for a variant is transformed into user-specified weights, which are in turn encoded into the ranking algorithm. Through its different modules, users can (i) rank a list of variants (ii) perform genotype filtering for case-control samples (iii) filter large amounts of high-throughput data based on user custom filter requirements and apply different models of inheritance (iv) perform downstream functional enrichment analysis through network visualization. Using networks, users can identify clusters of genes that belong to multiple ontology categories (like pathways, gene ontology, disease categories) and therefore expedite scientific discoveries. We demonstrate the utility of Variant Ranker to identify causal genes using real and synthetic datasets. Our results indicate that Variant Ranker exhibits excellent performance by correctly identifying and ranking the candidate genes CONCLUSIONS: Variant Ranker is a freely available web server on http://paschou-lab.mbg.duth.gr/Software.html . This tool will enable users to prioritise potentially causal variants and is applicable to a wide range of sequencing data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hereditary persistence of fetal hemoglobin (HPFH) is characterized by persistent high levels of fetal hemoglobin (HbF) in adults. Several contributory factors, both genetic and environmental, have ...been identified but others remain elusive. HPFH was found in 10 of 27 members from a Maltese family. We used a genome-wide SNP scan followed by linkage analysis to identify a candidate region on chromosome 19p13.12-13. Sequencing revealed a nonsense mutation in the KLF1 gene, p.K288X, which ablated the DNA-binding domain of this key erythroid transcriptional regulator. Only family members with HPFH were heterozygous carriers of this mutation. Expression profiling on primary erythroid progenitors showed that KLF1 target genes were downregulated in samples from individuals with HPFH. Functional assays suggested that, in addition to its established role in regulating adult globin expression, KLF1 is a key activator of the BCL11A gene, which encodes a suppressor of HbF expression. These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Specific Learning Disorder (SLD) is a multifactorial, neurodevelopmental disorder which may involve persistent difficulties in reading (dyslexia), written expression and/or mathematics. Dyslexia is ...characterized by difficulties with speed and accuracy of word reading, deficient decoding abilities, and poor spelling. Several studies from different, but complementary, scientific disciplines have investigated possible causal/risk factors for SLD. Biological, neurological, hereditary, cognitive, linguistic-phonological, developmental and environmental factors have been incriminated. Despite worldwide agreement that SLD is highly heritable, its exact biological basis remains elusive. We herein present: (a) an update of studies that have shaped our current knowledge on the disorder’s genetic architecture; (b) a discussion on whether this genetic architecture is ‘unique’ to SLD or, alternatively, whether there is an underlying common genetic background with other neurodevelopmental disorders; and, (c) a brief discussion on whether we are at a position of generating meaningful correlations between genetic findings and anatomical data from neuroimaging studies or specific molecular/cellular pathways. We conclude with open research questions that could drive future research directions.
Gilles de la Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder that is characterized by multiple motor and phonic tics. It has a complex etiology with multiple genes likely ...interacting with environmental factors to lead to the onset of symptoms. The genetic basis of the disorder remains elusive. However, multiple resources and large-scale projects are coming together, launching a new era in the field and bringing us on the verge of discovery. The large-scale efforts outlined in this report are complementary and represent a range of different approaches to the study of disorders with complex inheritance. The Tourette Syndrome Association International Consortium for Genetics (TSAICG) has focused on large families, parent-proband trios and cases for large case-control designs such as genomewide association studies (GWAS), copy number variation (CNV) scans, and exome/genome sequencing. TIC Genetics targets rare, large effect size mutations in simplex trios, and multigenerational families. The European Multicentre Tics in Children Study (EMTICS) seeks to elucidate gene-environment interactions including the involvement of infection and immune mechanisms in TS etiology. Finally, TS-EUROTRAIN, a Marie Curie Initial Training Network, aims to act as a platform to unify large-scale projects in the field and to educate the next generation of experts. Importantly, these complementary large-scale efforts are joining forces to uncover the full range of genetic variation and environmental risk factors for TS, holding great promise for identifying definitive TS susceptibility genes and shedding light into the complex pathophysiology of this disorder.
Introduction
Autoimmune disorders (ADs) are a group of about 80 disorders that occur when self-attacking autoantibodies are produced due to failure in the self-tolerance mechanisms. ADs are polygenic ...disorders and associations with genes both in the human leukocyte antigen (HLA) region and outside of it have been described. Previous studies have shown that they are highly comorbid with shared genetic risk factors, while epidemiological studies revealed associations between various lifestyle and health-related phenotypes and ADs.
Methods
Here, for the first time, we performed a comparative polygenic risk score (PRS) - Phenome Wide Association Study (PheWAS) for 11 different ADs (Juvenile Idiopathic Arthritis, Primary Sclerosing Cholangitis, Celiac Disease, Multiple Sclerosis, Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Type 1 Diabetes, Systemic Lupus Erythematosus, Vitiligo Late Onset, Vitiligo Early Onset) and 3,254 phenotypes available in the UK Biobank that include a wide range of socio-demographic, lifestyle and health-related outcomes. Additionally, we investigated the genetic relationships of the studied ADs, calculating their genetic correlation and conducting cross-disorder GWAS meta-analyses for the observed AD clusters.
Results
In total, we identified 508 phenotypes significantly associated with at least one AD PRS. 272 phenotypes were significantly associated after excluding variants in the HLA region from the PRS estimation. Through genetic correlation and genetic factor analyses, we identified four genetic factors that run across studied ADs. Cross-trait meta-analyses within each factor revealed pleiotropic genome-wide significant loci.
Discussion
Overall, our study confirms the association of different factors with genetic susceptibility for ADs and reveals novel observations that need to be further explored.
We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution ...to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Pituitary adenomas are common neoplasms of the anterior pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause pituitary adenoma predisposition ...(PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of pituitary adenomas. To evaluate the role of AIP in pituitary adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected pituitary adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of pituitary adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 adenomas: 12 AIP mutation-positive versus 38 mutation-negative pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.
Gilles de la Tourette Sydrome (TS) is a childhood onset neurodevelopmental disorder, characterized phenotypically by the presence of multiple motor and vocal tics. It is often accompanied by multiple ...psychiatric comorbidities, with Attention Deficit/Hyperactivity Disorder (ADHD) among the most common. The extensive co-occurrence of the two disorders suggests a shared genetic background. A major step toward the elucidation of the genetic architecture of TS was undertaken by the first TS Genome-wide Association Study (GWAS) reporting 552 SNPs that were moderately associated with TS (p < 1E-3). Similarly, initial ADHD GWAS attempts and meta-analysis were not able to produce genome-wide significant findings, but have provided insight to the genetic basis of the disorder. Here, we examine the common genetic background of the two neuropsychiatric phenotypes, by meta-analyzing the 552 top hits in the TS GWAS with the results of ADHD first GWASs. We identify 19 significant SNPs, with the top four implicated genes being TBC1D7, GUCY1A3, RAP1GDS1, and CHST11. TBCD17 harbors the top scoring SNP, rs1866863 (p:3.23E-07), located in a regulatory region downstream of the gene, and the third best-scoring SNP, rs2458304 (p:2.54E-06), located within an intron of the gene. Both variants were in linkage disequilibrium with eQTL rs499818, indicating a role in the expression levels of the gene. TBC1D7 is the third subunit of the TSC1/TSC2 complex, an inhibitor of the mTOR signaling pathway, with a central role in cell growth and autophagy. The top genes implicated by our study indicate a complex and intricate interplay between them, warranting further investigation into a possibly shared etiological mechanism for TS and ADHD.
The manifestation of Specific Learning Disorder (SLD) during adulthood is one of the least examined research areas among the relevant literature. Therefore, the adult population with SLD is ...considered a "rare" and "unique" population of major scientific interest. The aim of the current study was to investigate, describe, and analyze the clinical, academic, and socio-demographic characteristics, and other everyday functioning life-skills of adults with SLD, in an attempt to shed more light on this limited field of research. The overall sample consisted of 318 adults, who were assessed for possible SLD. The diagnostic procedure included self-report records (clinical interview), psychometric/cognitive, and learning assessments. The main finding of the study was that SLD, even during adulthood, continues to affect the individuals' well-being and functionality in all of their life domains. There is an ongoing struggle of this population to obtain academic qualifications in order to gain vocational rehabilitation, as well as a difficulty to create a family, possibly resulting from their unstable occupational status, their financial insecurity, and the emotional/self-esteem issues they usually encounter, due to their ongoing learning problems. Moreover, the various interpersonal characteristics, the comorbidity issues, and the different developmental backgrounds observed in the clinical, academic, personal, social, and occupational profiles of the participants, highlight the enormous heterogeneity and the continuum that characterizes SLD during adulthood. We conclude that there is an imperative need for further research and the construction of more sufficient tools for the assessment and diagnosis of SLD during adulthood, which will take into account the developmental challenges and milestones in a series of domains, in order to assist this "vulnerable" population with their life struggles.
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