A rare de novo unbalanced complex rearrangement involving chromosomes 12, 18 and 20 in a child with dysmorphic features

Complex chromosomal rearrangements (CCRs) are rare structural abnormalities that involve three or more breakpoints located on two or more chromosomes and are often associated with developmental delay, mental retardation and congenital anomalies. Here, we report the case of a rare de novo CCR in a girl who was 9 months old when first reported to us. At 15 months old, her clinical features included marked hypotonia, severe psychomotor delay, progressive postnatal microcephaly, strabismus, depressed nasal root, hands and feet malformations, heart defects, recurrent respiratory infections and bilateral hearing deficit still in study. Conventional cytogenetic analysis revealed an unbalanced complex rearrangement, involving chromosomes 12, 18 and 20, and an apparent loss of material of chromosome 18 resulting from an interstitial deletion. Further molecular cytogenetic studies were performed: whole chromosome painting probes for the involved chromosomes and chromosomal comparative genomic hybridization. These studies revealed that apparently no other chromosomes were involved and confirmed a del(18)(q21.1q22) of approximately 17 Mb on the derivative chromosome 18. The latter chromosome also had material from der(12) to der(20) in its constitution. As most CCRs involving chromosome 18q show rearrangements in the q21, some authors argue that this region might be a breakpoint “hotspot”. On the other hand, cases of single deletions on 18q are predominantly terminal. Interstitial deletions are much rarer, and to our knowledge, this is the first report of a CCR with a del(18)(q21.1q22). The phenotype of patients with deletions within this region, reported so far, seems very similar to the one of our patient, and this may contribute to a better understanding of the genotype–phenotype correlation in this type of structural abnormalities

Monozygotic twins concordant for common variable immunodeficiency : strikingly similar clinical and immune profile associated with a polygenic burden

Copyright © 2019 Silva, Fonseca, Pereira, Silva, Barbosa, Serra-Caetano, Blanco, Rosmaninho, Pérez-Andrés, Sousa, Raposo, Gama-Carvalho, Victorino, Hammarstrom and Sousa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Monozygotic twins provide a unique opportunity to better understand complex genetic diseases and the relative contribution of heritable factors in shaping the immune system throughout life. Common Variable Immunodeficiency Disorders (CVID) are primary antibody defects displaying wide phenotypic and genetic heterogeneity, with monogenic transmission accounting for only a minority of the cases. Here, we report a pair of monozygotic twins concordant for CVID without a family history of primary immunodeficiency. They featured a remarkably similar profile of clinical manifestations and immunological alterations at diagnosis (established at age 37) and along the subsequent 15 years of follow-up. Interestingly, whole-exome sequencing failed to identify a monogenic cause for CVID, but unraveled a combination of heterozygous variants, with a predicted deleterious impact. These variants were found in genes involved in relevant immunological pathways, such as JUN, PTPRC, TLR1, ICAM1, and JAK3. The potential for combinatorial effects translating into the observed disease phenotype is inferred from their roles in immune pathways, namely in T and B cell activation. The combination of these genetic variants is also likely to impose a significant constraint on environmental influences, resulting in a similar immunological phenotype in both twins, despite exposure to different living conditions. Overall, these cases stress the importance of integrating NGS data with clinical and immunological phenotypes at the single-cell level, as provided by multi-dimensional flow-cytometry, in order to understand the complex genetic landscape underlying the vast majority of patients with CVID, as well as those with other immunodeficiencies.This work received funding from PAC - PRECISE - LISBOA-01-0145-FEDER-016394, co-funded by FEDER through POR Lisboa 2020 - Programa Operacional Regional de Lisboa PORTUGAL 2020 and Fundação para a Ciência e a Tecnologia; and UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado. Work in MG-C lab is supported by UID/MULTI/04046/2019 Research Unit grant from FCT, Portugal (to BioISI) and FCT research grant PTDC/BIA-CEL/29257/2017.info:eu-repo/semantics/publishedVersio

Genetic Polymorphisms of the Epidermal Growth Factor and Related Receptor in Non-Small Cell Lung Cancer—A Review of the Literature

Learning Objectives After completing this course, the reader will be able to: Describe the role played by EGF and EGFR in lung carcinogenesis.Discuss how different polymorphic alleles from the EGF and EGFR genes may affect drug response.Evaluate the value of determining the presence of EGF and EGFR polymorphisms in NSCLC patients for daily clinical practice. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.co

NON-HERLITZ JUNCTIONAL EPIDERMOLYSIS BULLOSA - THE IMPORTANCE OF PRENATAL DIAGNOSIS

A epidermólise bolhosa juncional é uma genodermatose caracterizada por fragilidade cutânea e formação de erosões e bolhas a nível da junção dermo-epidérmica, após trauma minor. Reportamos o caso clínico de um recém-nascido, sexo masculino, caucasiano, com erupção cutânea caracterizada por bolhas tensas e erosões nas mãos, abdómen e couro cabeludo. Realizou-se uma biopsia cutânea para imunoflurescência directa com painel de anticorpos, que foi compatível com o diagnóstico de epidermólise bolhosa juncional não-Herlitz. No estudo genético identificou-se 2 mutações no gene COL17A1. Destaca-se nos antecedentes familiares, um irmão com dermatose bolhosa, falecido na terceira semana de vida por intercorrência infeciosa, sem ter sido possível efectuar o diagnóstico definitivo que possibilitasse o diagnóstico pré-natal. Salientamos a importância da referenciação rápida destes doentes a centros especializados, de forma a possibilitar o diagnóstico precoce desta patologia, uma orientação clínica adequada e um correto aconselhamento genético, incluindo o diagnóstico pré-natal em futuras gravidezes.Junctional epidermolysis bullosa is a group of inherited blistering diseases characterized by increased skin fragility, blisters and erosions after minor trauma, due to tissue cleavage at the dermal-epidermal junction. We report the case of a male Caucasian infant, born with erosions and tense blisters on the hands, abdomen and scalp. Immunoflurescence antigen mapping revealed paucity of collagen XVII immunolabelling, compatible with the diagnosis of non-Herlitz junctional epidermolysis bullosa. Molecular analysis of the COL17A1 gene revealed compound heterozygosity for two frameshift mutations. Family history was positive for a brother with a bullous dermatosis, who died from sepsis on the 3rd week of life without a definitive diagnosis that could enable precise risk estimation and prenatal diagnosis. We emphasize the importance of rapid referral to specialized centers, to provide early accurate diagnosis, adequate clinical management and prenatal diagnosis in subsequent pregnancies

Bi-allelic variants in COQ8B, a gene involved in the biosynthesis of coenzyme Q10, lead to non-syndromic retinitis pigmentosa

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.Retinitis pigmentosa (RP) is a Mendelian disease characterized by gradual loss of vision, due to the progressive degeneration of retinal cells. Genetically, it is highly heterogeneous, with pathogenic variants identified in more than 100 genes so far. Following a large-scale sequencing screening, we identified five individuals (four families) with recessive and non-syndromic RP, carrying as well bi-allelic DNA changes in COQ8B, a gene involved in the biosynthesis of coenzyme Q10. Specifically, we detected compound heterozygous assortments of five disease-causing variants (c.187C>T [p.Arg63Trp], c.566G>A [p.Trp189Ter], c.1156G>A [p.Asp386Asn], c.1324G>A [p.Val442Met], and c.1560G>A [p.Trp520Ter]), all segregating with disease according to a recessive pattern of inheritance. Cell-based analysis of recombinant proteins deriving from these genotypes, performed by target engagement assays, showed in all cases a significant decrease in ligand-protein interaction compared to the wild type. Our results indicate that variants in COQ8B lead to recessive non-syndromic RP, possibly by impairing the biosynthesis of coenzyme Q10, a key component of oxidative phosphorylation in the mitochondria.publishersversionpublishe

Prognostic stratification of adult primary glioblastoma multiforme patients based on their tumor gene amplification profiles

Several classification systems have been proposed to address genomic heterogeneity of glioblastoma multiforme, but they either showed limited prognostic value and/or are difficult to implement in routine diagnostics. Here we propose a prognostic stratification model for these primary tumors based on tumor gene amplification profiles, that might be easily implemented in routine diagnostics, and potentially improve the patients management. Gene amplification profiles were prospectively evaluated in 80 primary glioblastoma multiforme tumors using single-nucleotide polymorphism arrays and the results obtained validated in publicly available data from 267/347 cases. Gene amplification was detected in 45% of patients, and chromosome 7p11.2 including the EGFR gene, was the most frequently amplified chromosomal region – either alone (18%) or in combination with amplification of DNA sequences in other chromosomal regions (10% of cases). Other frequently amplified DNA sequences included regions in chromosomes 12q(10%), 4q12(7%) and 1q32.1(4%). Based on their gene amplification profiles, glioblastomas were subdivided into: i) tumors with no gene amplification (55%); ii) tumors with chromosome 7p/EGFR gene amplification (with or without amplification of other chromosomal regions) (38%); and iii) glioblastoma multiforme with a single (11%) or multiple (6%) amplified DNA sequences in chromosomal regions other than chromosome 7p. From the prognostic point of view, these amplification profiles showed a significant impact on overall survival of glioblastoma multiforme patients (p>0.001). Based on these gene amplification profiles, a risk-stratification scoring system was built for prognostic stratification of glioblastoma which might be easily implemented in routine diagnostics, and potentially contribute to improved patient management.This work was supported by RETICC RD06/0020/0035, RD06/0020/0059 and RD12/0036/0048 grants from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, (Madrid, Spain and FONDOS FEDER), AES PI16/000476 (Instituto de Salud Carlos III, Madrid, Spain and FONDOS FEDER), GRS909A14 (JCYL) and CB16/12/00400 grant (CIBERONC, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and FONDOS FEDER)

The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.

Inherited retinal diseases (IRDs) are a group of ocular conditions characterized by an elevated genetic and clinical heterogeneity. They are transmitted almost invariantly as monogenic traits. However, with more than 280 disease genes identified so far, association of clinical phenotypes with genotypes can be very challenging, and molecular diagnosis is essential for genetic counseling and correct management of the disease. In addition, the prevalence and the assortment of IRD mutations are often population-specific. In this work, we examined 230 families from Portugal, with individuals suffering from a variety of IRD diagnostic classes (270 subjects in total). Overall, we identified 157 unique mutations (34 previously unreported) in 57 distinct genes, with a diagnostic rate of 76%. The IRD mutational landscape was, to some extent, different from those reported in other European populations, including Spanish cohorts. For instance, the EYS gene appeared to be the most frequently mutated, with a prevalence of 10% among all IRD cases. This was, in part, due to the presence of a recurrent and seemingly founder mutation involving the deletion of exons 13 and 14 of this gene. Moreover, our analysis highlighted that as many as 51% of our cases had mutations in a homozygous state. To our knowledge, this is the first study assessing a cross-sectional genotype-phenotype landscape of IRDs in Portugal. Our data reveal a rather unique distribution of mutations, possibly shaped by a small number of rare ancestral events that have now become prevalent alleles in patients

Anesthesia of Epinephelus marginatus with essential oil of Aloysia polystachya: an approach on blood parameters

This study investigated the anesthetic potential of the essential oil (EO) of Aloysia polystachya in juveniles of dusky grouper (Epinephelus marginatus). Fish were exposed to different concentrations of EO of A. polystachya to evaluate time of induction and recovery from anesthesia. In the second experiment, fish were divided into four groups: control, ethanol and 50 or 300 mu L L-1 EO of A. polystachya, and each group was submitted to induction for 3.5 min and recovery for 5 or 10 min. The blood gases and glucose levels showed alterations as a function of the recovery times, but Na+ and K+ levels did not show any alteration. In conclusion, the EO from leaves of A. polystachya is an effective anesthetic for dusky grouper, because anesthesia was reached within the recommended time at EO concentrations of 300 and 400 mu L L-1. However, most evaluated blood parameters showed compensatory responses due to EO exposure.Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul/Programa de Apoio a Nucleos de Excelencia (FAPERGS/PRONEX) [10/0016-8]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [470964/2009-0]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brazil (CAPES)info:eu-repo/semantics/publishedVersio

Manual de mentoria : Programa do Politécnico de Viseu

A implementação dos princípios da educação inclusiva no Ensino Superior (ES) é um desafio à própria academia, docentes e estudantes, concretizável através da implementação de Programas de Tutoria/Mentoria. A educação inclusiva foi originalmente desenvolvida para estudantes mais jovens, antes da sua aplicação ao ES. No entanto, à medida que aumenta a heterogeneidade de estudantes no ES, tem aumentado também a necessidade de implementação de práticas inclusivas neste contexto académico. A missão das instituições de ES centra-se na promoção do desempenho e na preparação dos estudantes para a competitividade global, promovendo a excelência educacional e garantindo a igualdade no acesso. Cada vez mais as instituições de ensino superior (IES) têm incentivado e atraído estudantes de diversas origens e experiências, requerendo esforços para criar comunidades académicas inclusivas e acolhedoras para todos os estudantes. Com esta nova realidade, as IES têm procurado desenvolver estratégias de inclusão educativa em que as premissas passam por reconhecer a importância de um trabalho centrado na diversidade, equidade, inclusão de todos os estudantes, e restante comunidade académica, independentemente das suas características pessoais, situacionais ou culturais (Newman & Conway, 2016, pp. 100-101). No contexto de práticas inclusivas no ES, assume toda a importância fornecer aos estudantes o acesso a orientações que os levem a sentir-se plenamente incluídos, tendo em conta a prevalência da diversidade dos estudantes que ingressam no ES. A mentoria/tutoria pode ser eficaz no tratamento de questões-chave e problemas que as instituições do ES atualmente enfrentam, incluindo a necessidade de aumentar as taxas de conclusão dos cursos, reduzir o abandono escolar e as desigualdades nos resultados em grupos sub-representados, bem como ampliar a participação de todos os estudantes na vida académica, sem qualquer exclusão. Por outro lado, os estudantes também enfrentam muitos desafios, decorrentes do desconhecimento da organização e dinâmica institucional, como carga horária, quantidade e diversidade de matéria lecionada, ambiente académico e meio envolvente, processo no qual, a experiência prévia do mentor pode ser fundamental. Os estudantes envolvidos em programas de mentoria/tutoria desenvolvem mais conhecimento teórico e prático, com aplicação na futura vida profissional (Arnesson & Albinsson, 2017, pp. 202-203). Os programas de mentoria/tutoria definem-se como uma troca de conhecimentos e experiências entre mentor e mentorado. Além disso, a orientação é descrita como um processo democrático em que os pensamentos, as reflexões e os conhecimentos são aprofundados e resultam em práticas inclusivas. Um mentor é uma pessoa que contribui com o seu conhecimento, experiência e perspetivas, ou seja, está subjacente a ideia de que o mentor dá orientação ao mentorado no seu desenvolvimento pessoal e académico. O mentor, neste processo, desenvolve-se profissionalmente e o mentorado desenvolve-se a nível psicossocial. O mentor também pode ser descrito como uma pessoa sensata que tem interesse no apoio às pessoas menos experientes. Na prática, a mentoria/tutoria pode ser resumida como uma combinação de apoio emocional e prático (Arnesson & Albinsson, 2017, p. 203).info:eu-repo/semantics/publishedVersio