scholarly journals Psychomotor Delay in a Child with FGFR3 G380R Pathogenic Mutation Causing Achondroplasia

2021 ◽  
Author(s):  
Mahmut C. Ergoren ◽  
Erdal Eren ◽  
Elena Manara ◽  
Stefano Paolacci ◽  
Pinar Tulay ◽  
...  
Keyword(s):  
De Novo ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Pathogenic Mutation ◽  
Phenotypic Characteristics ◽  
Psychomotor Delay ◽  
Fgfr3 Gene ◽  
Proliferation And Differentiation ◽  
Common Causes ◽  
The Common

AbstractAchondroplasia (ACH) is a hereditary disorder of dwarfism that is caused by the aberrant proliferation and differentiation of chondrocyte growth plates. The common findings of macrocephaly and facial anomalies accompany dwarfism in these patients. Fibroblast growth factor receptor 3 (FGFR3) gene mutations are common causes of achondroplasia. The current study presents a case of 2-year-old male presenting with phenotypic characteristics of ACH. The interesting finding of the case is the presence of psychomotor delay that is not very common in these patients. Clinical exome sequencing analyzing 4.813 disease causing genes revealed a de novo c.1138G > A mutation within the FGFR3 gene. In conclusion, the mutation confirms the clinical diagnosis of ACH, and it seems to be causing the psychomotor delay in this patient.

scholarly journals FGFR3 overexpression is a useful detection tool for FGFR3 fusions and sequence variations in glioma

2020 ◽  
Author(s):  
Jens Schittenhelm ◽  
Lukas Ziegler ◽  
Jan Sperveslage ◽  
Michel Mittelbronn ◽  
David Capper ◽  
...  
Keyword(s):  
Coiled Coil ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Diagnostic Tools ◽  
Wild Type ◽  
Rt Pcr ◽  
Fgfr3 Gene ◽  
Detection Tool ◽  
Sequence Variations ◽  
Gene Panel Sequencing

Abstract Background Fibroblast growth factor receptor (FGFR) inhibitors are currently used in clinical development. A subset of glioblastomas carries gene fusion of FGFR3 and transforming acidic coiled-coil protein 3. The prevalence of other FGFR3 alterations in glioma is currently unclear. Methods We performed RT-PCR in 101 glioblastoma samples to detect FGFR3-TACC3 fusions (“RT-PCR cohort”) and correlated results with FGFR3 immunohistochemistry (IHC). Further, we applied FGFR3 IHC in 552 tissue microarray glioma samples (“TMA cohort”) and validated these results in two external cohorts with 319 patients. Gene panel sequencing was carried out in 88 samples (“NGS cohort”) to identify other possible FGFR3 alterations. Molecular modeling was performed on newly detected mutations. Results In the “RT-PCR cohort,” we identified FGFR3-TACC3 fusions in 2/101 glioblastomas. Positive IHC staining was observed in 73/1024 tumor samples of which 10 were strongly positive. In the “NGS cohort,” we identified FGFR3 fusions in 9/88 cases, FGFR3 amplification in 2/88 cases, and FGFR3 gene mutations in 7/88 cases in targeted sequencing. All FGFR3 fusions and amplifications and a novel FGFR3 K649R missense mutation were associated with FGFR3 overexpression (sensitivity and specificity of 93% and 95%, respectively, at cutoff IHC score > 7). Modeling of these data indicated that Tyr647, a residue phosphorylated as a part of FGFR3 activation, is affected by the K649R mutation. Conclusions FGFR3 IHC is a useful screening tool for the detection of FGFR3 alterations and could be included in the workflow for isocitrate dehydrogenase (IDH) wild-type glioma diagnostics. Samples with positive FGFR3 staining could then be selected for NGS-based diagnostic tools.

scholarly journals Two Siblings with Kaufman Oculocerebrofacial Syndrome Resembling Oculoauriculovertebral Spectrum

2021 ◽  
Vol 12 (2) ◽  
pp. 106-111
Author(s):  
Gizem Ürel-Demir ◽  
Büşra Aydın ◽  
Beren Karaosmanoğlu ◽  
Özlem Akgün-Doğan ◽  
Ekim Zihni Taşkıran ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Autosomal Recessive Disorder ◽  
Pathogenic Mutation ◽  
Genetic Alterations ◽  
High Rate ◽  
Facial Features ◽  
Psychomotor Delay ◽  
Oculoauriculovertebral Spectrum

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder which represents a phenotype mainly involving craniofacial and neurodevelopmental manifestations due to <i>UBE3B</i> gene mutations. The vast majority of the affected individuals exhibit microcephaly, eye abnormalities, and typical facial gestalt including blepharophimosis, ptosis, telecanthus, upslanting palpebral fissures, dysplastic ears, and micrognathia. We encountered 2 siblings in whom severe psychomotor delay, distinctive facial features, hearing loss, and respiratory distress were observed. Some clinical manifestations of the patients, including epibulbar dermoid, microtia, and multiple preauricular tags, were reminiscent of the oculoauriculovertebral spectrum. However, 2 affected siblings exhibited a similar clinical picture consisting of microcephaly, severe developmental and cognitive disabilities, failure to thrive, and dysmorphic features, which were not fully consistent with oculoauriculovertebral spectrum. Also, hypoplastic nails, considered as a core manifestation of Coffin-Siris syndrome, were present in our patients. Therefore, whole-exome sequencing was carried out in order to identify the underlying genetic alterations, contributing to the complex phenotype shared by the 2 siblings. A homozygous pathogenic mutation was found in both affected siblings in the <i>UBE3B</i> gene which caused Kaufman oculocerebrofacial syndrome. Kaufman oculocerebrofacial syndrome should be considered among the autosomal recessive causes of blepharophimosis-mental retardation syndromes, particularly in populations with a high rate of consanguineous marriages, even if there are dysmorphic facial features that are not typically associated with the phenotype.

scholarly journals A De Novo Deletion of Chromosome 18p with Persistent Limb Tremor and Difficulty Speaking

2019 ◽  
Vol 5 (1) ◽  
pp. 41-47
Author(s):  
Aghil Esmaeili-Bandboni ◽  
◽  
Arash Davoudi ◽  
Forozan Milani ◽  
Sara Afzali ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Clinical Presentation ◽  
De Novo ◽  
The Other ◽  
Deletion Syndrome ◽  
Chromosome 18 ◽  
Chromosomal Structure ◽  
Early Stages ◽  
Common Causes ◽  
The Common

Background: The common causes of 18p deletion syndrome are spontaneous errors in the chromosomal structure in the early stages of human embryonic development. Clinical Presentation and Intervention: In this study, a 29-year-old girl was introduced with the features of deletion of chromosome 18. In addition, GTG banding karyotype revealed that this case had a deletion involving the short arm of chromosome 18. In comparison with the usual phenotype of 18p deletion, many phenotypical features of this case were similar to the other cases of 18p monosomy. Conclusion: However, two new features; difficulty in speaking and persistent limb tremor, were found that had not been observed in previous studies on the 18p deletion. Speaking was without obvious pronunciation, and the patient’s physical movements were always unbalanced. These two features can be new signs for 18p deletion syndrome.

scholarly journals From “Technical Newbies” to “Optimistic Politicians”

2019 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
James Prater ◽  
Konstantinos Kirytopoulos ◽  
Tony Ma
Keyword(s):  
Information Technology ◽  
Quantitative Research ◽  
Valuable Insight ◽  
Scheduling Problems ◽  
Information Technology Projects ◽  
Content Type ◽  
Common Causes ◽  
The Common ◽  
Project Estimation ◽  
Engineering Projects

Purpose Despite the advent of sophisticated control methods, there are still significant issues regarding late delivery of information technology projects. The purpose of this paper is to investigate the common causes of scheduling problems specifically in the information technology projects context. Design/methodology/approach Through a quantitative research, the importance of those causes, as well as the underpinning factors driving them, is explored. The causes are ranked according to their relative important index, and exploratory factor analysis is employed to reveal underlying dimensions (factors) of these causes. Findings From the analysis, four factors were extracted, namely, “Dataless Newbie,” “Technical Newbie,” “Pragmatic Futurist” and “Optimistic Politician.” These factors explain the different latent conditions that lead to scheduling problems in information technology projects. Practical implications The key contribution of this research is that it enlightens the latent conditions underpinning scheduling problems. Also, the evidence provides that schedule development for information technology projects is impacted by the same causes that impact engineering projects, and that applying a number of mitigation techniques widely used within the engineering area, such as reference class, would, no doubt, not only improve information technology schedules but also reduce the political pressures on the project manager. Originality/value This research provides a valuable insight into understanding the underlying factors for poor project estimation.

scholarly journals Genetic variants of the EGFR ligand-binding domain and their association with structural alterations in Arab cancer patients

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maryam Marzouq ◽  
Ali Nairouz ◽  
Noureddine Ben Khalaf ◽  
Sonia Bourguiba-Hachemi ◽  
Raed Quaddorah ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Patients ◽  
Genetic Variants ◽  
Growth Factor Receptor ◽  
Genomic Analysis ◽  
Egfr Ligand ◽  
Energetic State ◽  
Epidermal Growth ◽  
The Common ◽  
Heterozygous Form

Abstract Objective This study aimed to identify novel genetic variants in the CR2 extracellular domain of the epidermal growth factor receptor (EGFR) in healthy individuals and patients with six different types of adenocarcinoma, in Arabian peninsula populations. It also aimed to investigate the effects of these variants on the EGFR structure and their eventual relevance to tumorigenesis. Results We detected seven new EGFR genetic variants in 168 cancer patients and 114 controls. A SNP rs374670788 was more frequent in bladder cancer but not significantly associated to. However, a missense mutation (V550M) was significantly associated to colon, ovary, lung, bladder and thyroid cancer samples (p < 0.05). Three mutations (H590R, E602K and T605T) were found in the heterozygous form only in colon cancer patients. Genomic analysis of the synonymous mutation (G632G) showed that the T/A genotype could be associated to thyroid cancer in Arab patients (p < 0.05). An additional novel SNP rs571064657 was observed in control individuals. Computational analysis of the genetic variants revealed a reduction in the stabilization of the EGFR tethered form for both V550M and the common R521K variant with low energetic state (− ∆∆G). Molecular interactions analysis suggested that these mutations might affect the receptor’s function and promote tumorigenesis.

The domino gene of Drosophila encodes novel members of the SWI2/SNF2 family of DNA-dependent ATPases, which contribute to the silencing of homeotic genes

Development ◽  
2001 ◽  
Vol 128 (8) ◽  
pp. 1429-1441 ◽  
Author(s):  
M.L. Ruhf ◽  
A. Braun ◽  
O. Papoulas ◽  
J.W. Tamkun ◽  
N. Randsholt ◽  
...  
Keyword(s):  
Polytene Chromosomes ◽  
Gene Mutations ◽  
Polycomb Group ◽  
Protein Isoforms ◽  
Homeotic Genes ◽  
Loss Of Function ◽  
Trithorax Group ◽  
A Subunit ◽  
The Common ◽  
Hematopoietic Disorders

The Drosophila domino gene has been isolated in a screen for mutations that cause hematopoietic disorders. Generation and analysis of loss-of-function domino alleles show that the phenotypes are typical for proliferation gene mutations. Clonal analysis demonstrates that domino is necessary for cell viability and proliferation, as well as for oogenesis. domino encodes two protein isoforms of 3202 and 2498 amino acids, which contain a common N-terminal region but divergent C termini. The common region includes a 500 amino acid DNA-dependent ATPase domain of the SWI2/SNF2 family of proteins, which function via interaction with chromatin. We show that, although domino alleles do not exhibit homeotic phenotypes by themselves, domino mutations enhance Polycomb group mutations and counteract Trithorax group effects. The Domino proteins are present in large complexes in embryo extracts, and one isoform binds to a number of discrete sites on larval polytene chromosomes. Altogether, the data lead us to propose that domino acts as a repressor by interfering with chromatin structure. This activity is likely to be performed as a subunit of a chromatin-remodeling complex.

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