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Development of a diagnostic protocol, mutation search, and genotype-phenotype correlation in haematological and immunological diseases by targeted resequencing using three different gene panels
No full textIntroduction: Next Generation Sequencing (NGS) has driven the rapid increase in the number of recognizable inborn errors of immune system development and/or function often hampered by the wide heterogeneity of the many genetically diverse but phenotypically overlapping diseases. NGS has also led to the discovery of new genes implicated in well-defined biological pathways, revisiting frequencies and broadening their phenotypic spectrum.
Objectives: Identification of the genetic causes of already known and unknown immune-mediated diseases with immunedysregulation; improvement of our knowledge about clinically overlapping phenotypes through the genetic characterization of the corresponding patients; optimization of the diagnostic work-up in order to administer disease specific treatments to patients.
Methods: A total of 150 patients, selected based on a clinical history highly evocative for immune-dysregulation (peripheral and/or central cytopenia and/or lymphoprolipheration and/or autoimmunity or autoinflammation) and/or immunodeficiency were submitted to 3 custom gene panels of 146, 315 and 58 genes and sequenced through the Ion Personal Genome Machine (PGMTM) System. Based on
the clinical phenotype, frequency and impact on the protein, variants were selected and validate by standard Sanger sequencing.
Results: The mutation detection rates for these panels were 15/51 (29%), and 16/69 (23%) and 2/30 (6%), respectively, for a total of 35 pathogenic variants that correlate with the respective clinical phenotypes. The patients could be classified in: ALPS/ALPS-like (97, 26 of which diagnosed), cytopenia (33, 4 diagnosed), undefined autoinfiammatory (12, 2 diagnosed) and suspected immunodeficiency (8, 1 diagnosed). Moreover, variants of unknown significance (VUS) in potentially causative genes were also found in additional 14 patients (6/30; 4/51; 4/69). A number of variants, either pathogenic, likely pathogenic, or VUS have been detected in some cases at genes unexpected on the basis of the phenotypes, among which PRKCD, PIK3CD, IL7R, NCF1, TNFRSF13C, CASP8, thus confirming wide heterogeneity in the phenotypic spectrum associated with diseases sharing haemato-immune rheumatological features. Conversely, several clinically similar cases did not reveal any relevant mutation, thus reflecting a genetic heterogeneity that is far from being disclosed yet.
Conclusion: The NGS approach has demonstrated excellent performances in the 1) evaluation of large genes and mutation detection, 2) overall timeliness of the gene panels, relying on continuous literature updates, and 3) identification of unexpected phenotypes for well-defined monogenic disease and definition of different disease clinical entities characterized by overlapping phenotypes. By contrast, due to the remarkable variability in clinical presentations, defining the appropriate list of genes for a given phenotype represents one key difficulty in the design of these panels. In the near future we will have to focus on the functional study of the many variants, especially VUS, that have emerged in a massive study like our
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
PAPA and FMF in two siblings: possible amplification of clinical presentation? A case report
Get PDFBackground: Familial Mediterranean Fever is a monogenic autoinflammatory disease, typically characterized by recurrent attacks of fever, serositis, aphthous of oral mucosa, erythema.
“Pyogenic arthritis, pyoderma gangrenosum and acne syndrome” is a rare autoinflammatory disease with variable expression and typically involving joints and skin. Both the diseases are linked by the overproduction of IL-1.
Case presentation: We report on the case of two siblings affected by recurrent attacks of fever, oral aphthous stomatitis, abdominal pain, arthritis, undefined dermatitis at the hands, associated with increased AST, ALT, C-reactive protein, erythrocyte sedimentation rate, serum amyloid A, leucocytosis with neutrophilia. Infectious diseases were excluded. The genetic study for Familial Mediterranean Fever, tumor necrosis factor receptor-associated periodic syndrome, Mevalonate kinase deficiency, showed the homozygous mutation p.M680I of exon 10 in MEFV. Their parents were heterozygous for the same mutation p.M680I, however, the mother showed severe symptoms of FMF (recurrent attacks of fever, arthralgia and arthritis, abdominal pain, thoracic pain), the father showed recurrent pustulosis prevalent on the hands and limbs, with arthralgia and abdominal pain. Both the patients started colchicine, with an improvement in clinical manifestations and a reduction of serum amyloid A. For the atypical dermatologic signs present in the two siblings and in the father, the study of other autoinflammatory
syndromes was performed with next generation sequencing and showed the heterozygous rare missense mutation of unknown significance: p.(Val408Ile) of PSTPIP1 gene in the two siblings and in the mother, the father was negative. Canakinumab treatment was started in the younger patient, with the resolution of the clinical symptoms and the normalization of serum amyloid A.
Conclusions: Further studies are needed to better describe the correlation between genotype and phenotype in patients with PAPA syndrome and with PAPA syndrome associated with FMF, considering that the presence of mutations in both genes may amplify clinical presentation and evolution of both diseases
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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