Browsing by Author "Marques, B."
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- 47,XY,+del(X)(q21.31)/46,XY mosaicism in prenatal diagnosis - case report of a rare eventPublication . Ferreira, C.; Tarelho, A.; Marques, B.; Serafim, S.; Pedro, S.; Ferreira, A.; Correia, H.OBJECTIVES: Aneuploidies involving the sex chromosomes are the most common anomalies in humans. In many cases these anomalies are present in mosaic and may involve either the whole chromosome or just part of it. These anomalies constitute a challenge in prenatal diagnosis because it is generally very difficult to establish a reliable genotype-phenotype correlation. Here we report a rare event of a mosaic in which one cell line carries an additional abnormal X chromosome, with a terminal deletion at q21.31 region, and a normal XY constitution in the majority of the cells. METHODS: A healthy 36-year-old G1P1 woman was referred for prenatal diagnosis at 11+5 weeks of gestation for increased nuchal translucency. Chorionic villus biopsy was performed and molecular rapid aneuploidy result indicated an anomalous situation for the X chromosome in a male fetus. As the material was not sufficient to establish a culture an amniocentesis was performed at 17+3 weeks and karyotyping and microarray were performed in order to characterize the anomalous result. RESULTS: The results obtained indicated the presence of a mosaic involving an extra X chromosome with a terminal deletion, [47,XY,+del(Xq)/46,XY.arr[GRCh37] Xp22.33q21.31(169921_89283237)x1~2], which is compatible with a Klinefelter syndrome variant. CONCLUSIONS: Pregnancies affected by X chromosome aneuploidies diagnosed prenatally are at an increased risk of adverse fetal and neonatal outcomes. High quality information is critical for informed decision-making in pregnancy following a prenatal diagnosis of sex chromosome aneuploidy. The participant shall be able to understand the importance of breakpoints definition and the impact that a mosaicism situation have in prenatal diagnosis.
- Age-dependency of the prognostic impact of tumor genomics in localized resectable MYCN non-amplified neuroblastomas Report from the SIOPEN Biology Group on the LNESG TrialsPublication . Ambros, I.M.; Tonini, G.P.; Gross, N.; Mosseri, V.; Pötschger, U.; Beiske, K.; Berbegall, A.P.; Bénard, J.; Bown, N.; Caron, H.; Combaret, V.; Couturier, J.; Defferrari, R.; Delattre, O.; Jeison, M.; Kogner, P.; Lunec, J.; Marques, B.; Martinsson, T.; Mazzocco, K.; Noguera, R.; Schleiermacher, G.; Valent, A.; Van Roy, N.; Villamon, E.; Janousek, D.; Pribill, I.; Glogova, E.; Attiyeh, E.F.; Hogarty, M.D.; Monclair, T.; Holmes, K.; Valteau-Couanet, D.; Pearson ADJ, A.D.J.; Castel, V.; Tweddle, D.A.; Park, J.R.; Cohn, S.; Ladenstein, R.; Beck-Popovic, M.; De Bernardi, B.; Michon, J.; Ambros, P.F.BACKGROUND: Biology based treatment reduction, i.e. surgery alone also in case of not totally resected tumors, was advised in neuroblastoma patients with localized resectable disease without MYCN amplification. However, whether the genomic background of these tumors may influence outcome was unknown and therefore scrutinized in a meta-analysis comprising two prospective therapy studies and a ‘validation’ cohort. PATIENTS AND METHODS: Diagnostic samples were derived from 406 INSS stages 1/2A/2B tumors from three cohorts: LNESGI/II and COG. Genomic data were analyzed in two age groups (cut-off: 18 months) and quality controlled by the SIOPEN Biology Group. RESULTS: In both patient age groups stage 2 tumors led to similarly reduced event-free survival (5y-EFS: 83+3% versus 80+4%), but overall survival was only decreased in patients >18m (5y-OS: 97+1% versus 87+4%; p=0.001). In the latter age subgroup, only tumors with SCA led to relapses, with 11q loss as the strongest marker (5y-EFS: 40+15% versus 89+5%; p<0,001). Below 18m, EFS but not OS was decreased only in case of 1p loss (5y-EFS: 62+13% versus 85+3%; p=0,041). SCAs were associated with worse OS only in patients >18m but not <18m. CONCLUSION: The tumor genomic make-up of resectable non-MYCN amplified stage 2 neuroblastomas has a distinct age-dependent prognostic impact in neuroblastoma patients. While in the younger age group tumors with unfavourable (SCA) and favorable genetics showed relapses, both without worsening OS, in the older age group only tumors with unfavorable genetics led to relapses and decreased OS.
- O Biólogo Especialista em SaúdePublication . Sousa, A.; Marques, B.; Júlio, C.; Guia Pereira, A.; Correia, H.; Ávila, M.; Rendeiro, P.; Monteiro, M.; Lopo, S.; Pinheiro, J.; Cunha, N.; Figueiredo, H.; Correia, S.; Ramos, S.A presença do Biólogo com atividade na saúde teve nas últimas décadas notável incremento, em hospitais, institutos e centros de saúde, universidades, laboratórios privados e indústria, em particular nas áreas de investigação, análises clínicas, genética humana, embriologia/reprodução humana, entre outras. Persistem, todavia, alguns constrangimentos para estes profissionais de saúde, no acesso à profissão e na consequente atribuição de responsabilidades técnicas e científicas. Cabe à OBIO a defesa, regulação e certificação dos seus profissionais, bem como garantir códigos de conduta e formação contínua determinantes para a elevada qualidade que se espera destes. De igual modo, o CBHS assume as competências estatutárias na definição dos seus objetivos de forma a garantir o bom exercício da atividade profissional dos seus membros, e o reconhecimento destes pela Sociedade e Instituições.
- Characterization of a rare analphoid sSMC(7)Publication . Marques, B.; Brito, F.; Ferreira, Cristina; Correia, H.; Alves, C.; Amorim, A.; Pedro, S.
- Characterization of a rare analphoid supernumerary marker chromosome in mosaicPublication . Marques, B.; Alves, C.; Ferreira, C.; Correia, H.; Brito, F.; Pedro, S.; Amorim, M.Analphoid supernumerary marker chromosomes (SMCs) are a rare subclass of SMCs C-band-negative and devoid of alpha-satellite DNA. These marker chromosomes cannot be identified unambiguously by conventional banding techniques alone being necessary to apply molecular cytogenetic methods in favour of a detailed characterization. In this work we report an analphoid SMC involving the terminal long arm of chromosome 7, in 9 years-old boy with several dysmorphic features and severe development delay. Cytogenetic analysis revealed a mosaic karyotype with the presence of an extra SMC, de novo, in 20 % of lymphocytes and 73 % of fibroblast cells. FISH analysis with alpha-satellite probes for all chromosomes, whole chromosome painting probe for chromosome 7, and D7S427 and TelVysion 7q probes, allowed establishing the origin of the SMC as an analphoidmarker resulting of an invdup rearrangement of 7q36-qter region. Affimetrix CytoScan HD microarray analysis, redefined the SMC to arr[hg19] 7q35(143696249-159119707)×2~3, which correspond to a gain of 15.42 Mb and encloses 67 OMIM genes, 16 of which are associated to disease. This result, combined with detailed clinical description, will provide an important means for better genotype-phenotype correlation and a more suitable genetic counselling to the patient and his parents, despite the additional difficulty resulting from being a mosaic (expression varies in different tissues). Analphoid SMCs derived from chromosome 7 are very rare, with only three cases reported so far. With this case we hope contribute to a better understanding of this type of chromosome rearrangements which are difficult for genetic counselling.
- Chromosomal disorders and male infertilityPublication . Simão, L.; Caetano, I.; Pedro, S.; Silva, M.; Ambrósio, P.; Gonçalves, J.; Brito, F.; Marques, B.; Alves, C.; Serafim, S.; Geraldes, M.C.; Correia, H.Male factor infertility is considered a complex disorder with a largely unknown etiology that affects about 7% of men. In general, genetic abnormalities account for 15%-30% of condition and Y chromosome microdeletions are also frequent. The study, based on our casuistic, aimed at contributing to a better understanding of the genetic causes of infertility. A group of 410 idiopathic infertile men with non-obstructive azoospermia, oligozoospermia, or unknown semen quality (based on clinical evaluation and/or sperm counts) was retrospectively selected. Conventional karyotype was performed in all samples; Y microdeletion screen was performed in 247 samples. Forty two abnormal karyotypes (10.2%) were found, indicating an elevated frequency of chromosome abnormalities among the selected infertile men, as compared to that of newborn populations (≈0.4%). This frequency is higher than that reported in most similar studies that pointed to frequencies ranging from 2.2%-14.3%. Klinefelter´s syndrome was the most common chromosome disorder (4.9%). There were 18 cases with 47,XXY karyotype and 2 cases of mosaicism involving lines 47,XXY and 46,XY. Reciprocal translocations were identified in 10 cases (2.4%), particularly in men with unknown semen quality. Overall, reciprocal translocations have been found in approximately 1% of the infertile men and more commonly in azoospermics than in oligozoospermics. However, this type of association was not found in the present study. On the other hand, Y microdeletions were identified in 16/247 cases (6.5%), more frequently in azoospermics (13.3%, corresponding to 8/60 azoospermics). Among these 8 cases, 7 presented deletions at the AZFc region. The marked presence of chromosomal abnormalities and Y microdeletions enphasizes the relevance of studying both factors in infertile men to improve genetic counseling, to allow the development of appropriate therapies, and to expand the knowledge about the ethiology of male infertility.
- Classification of the dup 15q13.3 CNV: A National data collectionPublication . Sousa, A.; Serafim, S.; Santos, R.; Custódio, S.; Ávila, M.; Dupont, J.; Dias P, P.; Moldovan, O.; Melo, J.; Ferreira, S.; Pires, L.; Leão, M.; Sá, S.; Prior, C.; Alves, C.; Barreta, A.; Tarelho, A.; Marques, B.; Pedro, S.; Lopes, F.; Maciel, P.; Correia, H.; Dória, S.; Rendeiro, P.; Castedo, S.; Carreira, I.; Sousa, A.B.Introduction: The proximal region 15q11q14 is one of the most unstable regions in the human genome, with six recognizable break points (BP1-BP6). In 15q13.3 there is a recurrent small CNV (BP4-BP5) consisting of a 350-680 Kb duplication, encompassing the CHRNA7 gene, which encodes the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor. Although microdeletions of CHRNA7 are known to cause intellectual disability and neuropsychiatric phenotypes with high penetrance, the patogenicity of CHRNA7 duplications remains unclear. Microduplication 15q13.3 seems to be associated with a phenotypic spectrum of cognitive impairment and neuropsychiatric/neurobehavioral disorders. However, the penetrance of this CNV is considered incomplete since it is present in clinically unaffected individuals in the general population and it is frequently inherited from apparently clinically normal parents. Nonetheless, some pedigree studies have found a history of neuropsychiatric problems among carrier family members. This study aimed at re-evaluating the dup 15q13.3 CNV in national laboratories. Materials and Methods: Our study collected data on 15q13.3 microduplications in eight Portuguese genetics laboratories, among subjects referred for microarray. Results: Here we present a total of seventeen cases with dup 15q13.3. The subjects had somewhat variable phenotypes, with a bias towards developmental delay and autism spectrum disorders. Inheritance was established for eight of the subjects, and the majority originated from the father. We had no access to clinical data on carrier parents. No de novo CNV was found. All laboratories involved classified this variant as of uncertain significance. Discussion/Conclusion: To better determine whether this CNV is benign or pathogenic, careful characterization of patient and control cohorts must be performed, including detailed patient phenotyping, inheritance, clinical evaluation of carrier parents, prevalence in controls, as well as genetic functional studies. We strongly support the creation of a national database for uncertain CNVs in order to clarify the relevance of these recurrent findings, allowing a definitive classification in either pathogenic or benign.
- Clinical, cytogenetic and molecular findings of a “de novo” inv dup del (6q)Publication . Fonseca Silva, M.L.; Mota Freitas, M.; Candeias, C.; Ribeiro, J.; Oliva Teles, N.; Soares, G.; Tkachenko, N.; Marques, B.; Correia, H.Introduction: Complex rearrangements resulting in inverted duplications contiguous to a terminal deletion (inv dup del) were first reported for the short arm of chromosome 8 in1976. Since then this type of structural anomaly has been described for an increasing number of chromosomes. In these rearrangements, the concomitant presence of a deletion and a duplication has important consequences in genotype-phenotype correlations. The authors describe the clinical findings and the cytogenetic characterization of a rare inv dup del involving the long arm of chromosome 6. Material and methods: A girl aged 5 was referred for subtelomeric studies with the indication of psychomotor retardation, autistic features and stereotipies. Chromosome analysis with high resolution GTL-banding was performed on metaphases obtained from cultured peripheral blood lymphocytes. Molecular studies included MLPA (Kits P036 and P070, MRC-Holland), FISH with subtelomeric and whole chromosome painting probes specific for chromosome 6, and cCGH techniques. Results: Initial MLPA studies detected a subtelomeric deletion in the long arm of chromosome 6; the subsequent karyotype revealed a structurally abnormal chromosome 6 with additional material in the end of the long arm. FISH analysis showed the deletion and demonstrated that the extra material was derived from chromosome 6; cCGH tecnhiques defined the extension and confirmed the breakpoints of the duplicated segment. Thus this rearrangement was interpreted as an inv dup del (6q). Since parental karyotypes were normal, this anomaly was considered “de novo”. Discussion: As far as we know this is the first description of a patient presenting with a “de novo” inv dup del (6q). We compare the clinical features in this child with the previously reported cases with either an isolated terminal deletion or a duplication of distal 6q. The authors enhance the importance of the combination of high resolution banding with molecular studies in the characterization of this rare rearrangement.
- Diagnóstico pré-natal tardio de uma gestação com anomalias ecográficas e com duplicação da região 7q11.23Publication . Simão, L.; Serafim, S.; Ferreira, C.; Alves, C.; Brito, F.; Silva, M.; Furtado, J.; Viegas, M.; Pedro, S.; Marques, B.; Rodrigues, M.; Sá, J.; Castro, M.J.; Mendes, P.; Vassal, H.; Correia, H.Introdução: O diagnóstico pré-natal (DPN) atempado de anomalias cromossómicas em fetos com anomalias ecográficas é fundamental no prognóstico da gravidez, ou na sua possível interrupção. Assim, a realização das ecografias fetais nas semanas preconizadas é determinante para a gestão dos casos anormais. Descrevemos um caso de uma gravidez mal vigiada, com ecografia fetal realizada às 29 semanas de gestação, onde se identificou uma dilatação pielo-calicial grave no rim esquerdo e dúvida na área cardíaca. Objectivos: Evidenciar que a vigilância atempada das gestações conjuntamente com a análise por microarray aumenta a capacidade de diagnóstico em gestações com anomalias fetais detetadas ecograficamente.
- Hypomelanosis of Ito vs Pigmentary Mosaicism: a challenging diagnosisPublication . Antunes, D.; Kay, T.; Cabete, J.; Marques, B.; Brito, F.; Correia, H.; Nunes, L.Introdution: Since 1952 several case reports and case series of Hypomelanosis of Ito (HI) has described different associations with multiple extra cutaneous manifestations, being the neurological anomalies the most frequent and important ones. Methods: We report a 5-years-old girl, refered by dyschromia , minor dysmorphic features, strabism, ventricular septal heart defect and slight learning difficulties. The peripheral blood karyotype that was normal. Hypopigmented patches along Blaschko’s lines were observed. Other anomalies included a simian palm crease on right hand, persistency of fetal pads, and mild genu valgum/recurvatum. A skin biopsy for histopathological and cytogenetic studies was performed on a hypopigmented patch and a magnetic resonance imaging (MRI) of central nervous system (CNS) was requested. Results: Histopathological study of the skin was inconclusive. However, the cytogenetic study revealed the presence of mosaicism: one normal cell line and one abnormal cell line with monosomy of chromosome 18 and presence of a marker chromosome (46,XX,-18,+mar[22]/46,XX[28]) . Fluorescence in situ hybridization (FISH) technique identified the marker as a derivative of chromosome 18, comprising the centromeric region and a small portion of euchromatic material. CNS MRI was normal. Discussion: Some authors suggest that HI would be better designated as “pigmentary mosaicism”, following the hypothesis that the chromosomal abnormalities reported specifically disrupt pigmentary genes. Although numerous cases of mosaicism concerning chromosome 18 were previously described, this specific cytogenetic anomaly was not yet reported. The mild phenotype presented in this case suggests that mosaicism may have a low expression. Nevertheless, the loss genetic material in the abnormal cell line raises several questions about future outcomes, especially regarding the theoretical concern of a predisposition to certain malignancies and the difficulty of genetic counseling. This case illustrates the challenge of a diagnosis when facing a variety of phenotypes and reinforces the importance of karyotyping other tissues besides peripheral blood.
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