Percorrer por autor "Fortuna, Ana"
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- Citogenética de Próxima Geração: Implementação e primeiros resultados em PortugalPublication . David, Dezső; Oliva-Teles, Natália; Freixo, João; Fonseca e Silva, ML; Fortuna, Ana; Tkachenko, Natália; Carvalho, Inês; Marques, Mariana; Cardoso, Manuela; Fino, Joana; Marques, Bárbara; Alves, Ana Cristina; Dória, Sófia; Pinto de Moura, Carla; Marques Carreira, Isabel; Correia, Hildeberto; Gonçalves, Rui Miguel; Lavinha, João; Kay, Teresa; Talkowski, Michael; Morton, CynthiaIntrodução: As alterações cromossómicas estruturais provocam doenças de severidade variável que acarretam sofrimento individual e familiar signifi cativo. Para compreensão da sua etiologia e estabelecimento de um possível prognóstico, uma adequada correlação fenótipo-genótipo é fundamental. O presente estudo faz parte do projeto intitulado àCitogenética de Próxima Geração Irrompe nos Cuidados de Saúde e Contribui para Anotação do Genoma Humanoà, que visa a introdu- ção da sequenciação de próxima geração (NGS) na citogené- tica clínica, tirando partido dessa inovação única na deteção de variantes estruturais, com uma resolução de um nucleótido para a criação de uma citogenética de alto rendimento, catalisadora de notáveis avanços no diagnóstico clínico e resulta da colaboração entre seis Instituições nacionais e a Harvard Medical School. Estima-se que exista um número considerável de indivíduos portadores de diversas patologias, incluindo algumas de início tardio associadas a rearranjos genómicos por identifi car. Assim, é fundamental a identifi cação e a referência destes indivíduos com possíveis rearranjos cromossómicos associados a doenças.
- Diagnóstico e Tratamento de Doenças Lisossomais: relatório 2012Publication . Grupo de Trabalho Coordenador do Diagnóstico e Tratamento de Doenças Lisossomais; Fortuna, AnaRelatório anual do Grupo de Trabalho Coordenador do Diagnóstico e Tratamento de Doenças Lisossomais (GTCDTDL), relativo ao ano 2012, do qual se destaca a realização das seguintes atividades: − Discussão e avaliação de 43 casos clínicos relativos a pedidos de tratamento, ajuste de dose ou alteração do tratamento, mais 16 casos do que em 2011. Foram emitidos pareceres para Doença de Gaucher, Doença de Fabry, Mucopolissacaridoses tipo I, II e VI, Doença de Pompe e Doença de Niemann Pick tipo C. − Prossecução da compilação da documentação relativa aos doentes com a finalidade de constituir uma base de dados. − Avaliação atualizada e envio regular dos encargos mensais por doença e entidade prestadora dos cuidados de saúde, bem como a data de início e/ou suspensão das terapêuticas à Administração Central do Sistema de Saúde (ACSS). − Consolidação da constituição do grupo de trabalho e formulação de convite a consultores científicos, quando pertinente. − Compilação de documentação científica e informação de entidades europeias. − Organização logística interna e externa e de documentos de suporte, existindo formulários de registo dos dados individuais para solicitação de início e seguimento da terapêutica. − Estabelecimento e fortalecimento de contactos com instituições ou organismos relevantes (INFARMED, ACSS, DGS), associações de doentes (ex: APL, Raríssimas, Eurordis) e a indústria farmacêutica (Genzyme, Actelion, Biomarin, Shire). Em 2012, o GTCDTDL prosseguindo a sua missão de garantir a gestão e a coordenação a nível nacional do diagnóstico e tratamento das DLS, constatou que, apesar do número de doentes em tratamento continuar a aumentar, a política seguida pelo Grupo de trabalho de procurar individualizar melhor a dose terapêutica em cada doente reduzindo-a sempre que possível, aliada à redução dos preços pela indústria farmacêutica, tem permitido alguma contenção dos custos.
- Early results of next-gen cytogenetics implementation in PortugalPublication . David, Dezső; Freixo, João; Marques, Bárbara; Carvalho, Inês; Tkachenko, Natália; Oliva-Teles, Natália; Marques, Mariana; Cardoso, Manuela; Fino, Joana; Alves, Cristina; Fortuna, Ana; Sófia, Dória; Pinto de Moura, Carla; Correia, Hildeberto; Marques Carreira, Isabel; Sá, Joaquim; Gonçalves, Rui Miguel; Lavinha, João; Kay, Teresa; Talkowski, Michael; Morton, CynthiaBackground: Most approaches are insensitive to the full mutational spectrum of chromosome rearrangements associated with human developmental abnormalities. Therefore, our aim is to introduce next-generation sequencing (NGS) into clinical cytogenetics, creating a sequence-based NextGen Cytogenetics to catalyze a dramatic advancement in clinical diagnostics. Methods: Twenty families with chromosome rearrangement-associated diseases, including two prenatal (PN) cases, have been enrolled. Fourteen of these were also analyzed by NGS using large-insert paired-end libraries. Results: The majority of these cases were confirmed to be balanced reciprocal rearrangements, whereas 4 were complex chromosomal rearrangements including 1 of chromothripsis. Thus far, over 50 breakpoints were identified disrupting protein coding genes, lncRNAs, or intergenic regions, thus revealing candidate genes or genomic loci. These cases are further assessed for pathogenicity from positional effects on genes located within topological domains (TADs) containing the breakpoints using DECIPHER predictions of haploinsufficiency. In one PN case, the 16q24 breakpoint disrupts ANKRD11, etiologic in the autosomal dominant KBG syndrome (OMIM #148050), predicting an abnormal phenotype. The chromothripsis case, submitted as 46,XY,t(7;14)(q22;q32.1),inv(15)(q21.2q26.1), proved by NGS to carry two further deletions, at 3p12 (5.3 Mb) and 15q14 (488 kb), as well as an insertion of 644.4 kb from 15q14 into 3p14. The inv(15) is in fact a complex rearrangement of 15q with eight breakpoints. Conclusions: We demonstrate that NGS-based chromosomal rearrangement characterization leads to major improvements in identification of chromosomal aberrations and in prediction of clinical outcomes of postnatally and prenatally detected genomic rearrangements, and to contributions to human genome annotation.
- FXTAS is rare among Portuguese patients with movement disorders: FMR1 premutations may be associated with a wider spectrum of phenotypesPublication . Seixas, Ana; Vale, José; Jorge, Paula; Marques, Isabel; Santos, Rosário; Alonso, Isabel; Fortuna, Ana; Pinto-Basto, Jorge; Coutinho, Paula; Margolis, Russell; Sequeiros, Jorge; Silveira, IsabelThe fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansions of 55-200 CGG repeats in the 5'UTR of the FMR1 gene. These FMR1 premutation expansions have relatively high frequency in the general population. To estimate the frequency of FMR1 premutations among Portuguese males with non-familial, late-onset movement disorders of unknown etiology, we assessed CGG repeat size in males with disease onset after the age of 50 and negative or unknown family history for late-onset movement disorders, who were sent for SCA, HD, or PD genetic testing at a reference laboratory. The selected patients had a primary clinical diagnosis based on one of the following cardinal features of FXTAS: ataxia, tremor, or cognitive decline. A total of 86 subjects were genotyped for the CGG repeat in the FMR1 gene. We detected one patient with an expansion in the premutation range. The frequency of FMR1 premutations was 1.9% (1/54) in our group of patients with ataxia as the primary clinical feature, and 1.2% (1/86) in the larger movement disorders group. In the family of the FXTAS case, premutation-transmitting females presented a history of psychiatric symptoms, suggesting that, given the wide phenotypical expression of the premutation in females, neuropsychiatric surveillance is necessary. In conclusion, genetic testing for FXTAS should be made available to patients with adult-onset movement disorders to enable adequate genetic counseling to family members.
- Koolen-de Vries syndrome – National Case Series with clinical and molecular characterizationPublication . Soares, Marta P.; Rodrigues, Márcia; Dupont, Juliette; Medeira, Ana; Freixo, João; Nunes, Sofia; Cordeiro, Isabel; Travessa, André; Soares, Gabriela; Fortuna, Ana; Ramos, Fabiana; Sá, Joaquim; Rocha, Susana; Figueiredo, Cristina; Mendonça, Carla; Tapadinhas, Fernando; Silveira-Santos, Rosário; Custódio, Sónia; Barreta, Ana; Serafim, Sílvia; Correia, Hildeberto; Val, Mariana; Carreira, Isabel M.; Rendeiro, Paula; Sousa, Ana; Sousa, Ana BertaIntroduction: Koolen-de Vries Syndrome (KdVS) is a rare genetic condition, caused by a 17q21.31 microdeletion, or a pathogenic variant in KANSL1 gene. The clinical picture includes developmental delay (DD)/intellectual disability (ID) with expressive language particularly impaired, dysmorphisms, neonatal hypotonia, and friendly behaviour. Aim: To characterize at the molecular and clinical levels all patients in Portugal diagnosed with KdVS.
- Next-Gen Cytogenetics and the Hidden Complexity of Genomic or Chromosomal RearrangementsPublication . David, Dezső; Freixo, João; Carvalho, Inês; Tkachenko, Natalia; Oliva Teles, Natália; Marques, Bárbara; Alves, Ana Cristina; Fortuna, Ana; Sofia, Dória; Pinto de Moura, Carla; Gaspar, Isabel; Marques Carreira, Isabel; Sá, Joaquim; Gonçalves, Rui; Lavinha, João; Kay, Teresa; Correia, Hildeberto; Talkowski, Michael E.; Morton, Cynthia C.Human developmental abnormalities are devastating conditions that account for almost half of all full-term neonatal deaths in developed countries. For individuals who survive, congenital anomalies often confer lifelong disability and their impact on public health is profound. However, the genetic etiology and genomic architecture contributing to the vast majority of these conditions remain unknown. Separately, and in addition, the genetic etiologies of recurrent infertility remain to be elucidated. The current low resolution diagnostic techniques are insensitive to the full mutational spectrum contributing to human developmental abnormalities and infertility, the poor understanding of the molecular alterations introduced by genomic rearrangements, and the lack of a fully annotated human genome hinders predictive diagnostics. This study results from collaboration between a Portuguese Consortium including clinical geneticists and the Developmental Genome Anatomy Project (DGAP) from Harvard Medical School. First, a group of cases were comparatively analyzed using genomic array and Next-Generation Sequencing (NGS). Subsequently, NGS of whole-genome large-insert libraries was applied for the identification of genomic or chromosomal rearrangements at nucleotide resolution in a series of cases, including two prenatal samples. Presently, this high-throughput technology is the only approach able to identify the full spectrum of structural variants, in a time frame that allows its application even for prenatal samples.The introduction of NGS into clinical cytogenetics surely will create a high-throughput, sequence-based Next-Gen Cytogenetics that will catalyze a dramatic advancement in clinical diagnostics. Therefore the understanding of the molecular pathology of these chromosome rearrangement-associated developmental disorders and infertilities will contribute to an improved prediction of the phenotypic consequences of these rearrangements.
- Private dysferlin exon skipping mutation (c.5492G>A) with a founder effect reveals further alternative splicing involving exons 49-51Publication . Santos, Rosário; Oliveira, Jorge; Vieira, Emília; Coelho, Teresa; Carneiro, António Leite; Evangelista, Teresinha; Dias, Cristina; Fortuna, Ana; Geraldo, Argemiro; Negrão, Luís; Guimarães, António; Bronze-da-Rocha, ElsaThe allelic muscle disorders known as limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy and distal anterior compartment myopathy result from defects in dysferlin—a sarcolemma-associated protein involved in membrane repair. Mutation screening in the dysferlin gene (DYSF) enabled the identification of seven Portuguese patients presenting the variant c.5492G4A, which was observed to promote skipping of exon 49 (p.Gly1802ValfsX17). Several residually expressed products of alternative splicing also involving exons 50 and 51 were detected in the leukocytes and muscle of both patients and normal controls. Quantitative transcript analysis confirmed these results and revealed that D49/D50 transcripts were predominant in blood. Although the patients were apparently unrelated, the c.5492G4A mutation was found in linkage disequilibrium with a particularly rare haplotype in the population, corroborating the hypothesis of a common origin. Despite the presence of the same mutation on the same haplotype background, onset of the disease was heterogeneous, with either proximal or distal muscle involvement.
- A rare case of Beckwith–Wiedemann syndrome caused by a de novo microduplication at 11p15.5 of paternal originPublication . Ferreira, Cristina; Marques, Bárbara; Alves, Cristina; Barbosa, Mafalda; Fortuna, Ana; Reis-Lima, Margarida; Correia, HildebertoBeckwith–Wiedemann syndrome (BWS) is a disorder of growth regulation exhibiting somatic overgrowth and predisposition to paediatric tumours. With an incidence estimated at 1 in 13,700, it is caused by various epigenetic and/or genetic alterations associated with disturbances within two different 11p15 domains that are controlled by distinct imprinting control regions (ICR), ICR1 and ICR2. The majority of patients have abnormalities within ICR2 presenting hypomethylation, while less frequent aetiologies include mosaic paternal 11p uniparental disomy (11patUPD), maternally inherited mutations of the CDKN1C gene, and hypermethylation of ICR1. A few patients have cytogenetic abnormalities involving 11p15.5. Since the subgroups are associated with different recurrence risks, the identification of the molecular cause of BWS is particularly important for the follow-up of the patient and the genetic counselling of both the patient and the family. Here, we report a 13-year-old girl with clinical diagnosis of BWS presenting macrosomia, umbilical hernia, kidney abnormalities, hydramnius, prematurity, typical face, advanced bone age, moderate developmental delay, prominent occiput and forehead, round face, epicanthus, short nasal bridge, and microretrognathia. Cytogenetic analysis with highresolution banding showed an apparently normal karyotype. Microsatellite analysis and methylationspecific multiplex ligation-dependent probe amplification revealed a de novo microduplication at 11p15.5 of paternal origin. Duplication has a minimum size of 600 kb, covering only ICR1, not affecting ICR2. This sporadic case with a de novo duplication without other chromosomal abnormalities makes genotype–phenotype correlation difficult. As far as we know, this is one of the smallest duplications associated with BWS and is consistent with the independent regulation of ICR1 and ICR2. Our patient presented moderate developmental delay and craniofacial features typical of 11p15 duplication. Future studies exploiting this subtle 11p15.5 rearrangement will provide an important tool to further dissecting the genomics of BWS region and the pathogenesis of this imprinting disorder.
- Três rearranjos diferentes, três fenótipos diferentes :Estudo Familiar Cromossoma 14Publication . Lopes, Elisa; Silva, Isaltina; Mota Freitas, Manuela; Oliva Teles, Natalia; Fortuna, Ana; Correia, Hildeberto; Fonseca e Silva ML 1., Maria da LuzIntrodução – Cromossomas derivativos são o resultado de rearranjos estruturais que tanto podem ocorrer num só, como entre dois ou mais cromossomas. Estes rearranjos dão origem a cromossomas estruturalmente anormais, podendo resultar um fenótipo normal ou mais ou menos grave, dependendo do tipo de anomalia encontrada. Materiais e métodos – Caso índex: homem de 55 anos, referenciado para estudos de citogenética clássica (cariótipo com bandas GTG de alta resolução) e molecular (MLPA – kits P036 e P070 e FISH com sonda subtelomérica especifica para o cromossoma 14) por apresentar um quadro clínico de atraso mental. Posteriormente realizaram-se estudos citogenéticos a uma irmã com atraso cognitivo e baixa estatura, e a mais quatro familiares com fenótipos normais. Resultados – O cariótipo do caso índex revelou a existência de uma anomalia cromossómica estrutural desequilibrada num dos cromossomas 14, sugerindo uma deleção da banda 14q32, e uma duplicação do braço curto localizada na parte terminal do braço longo. Nos estudos de citogenética molecular, a técnica de MLPA identificou uma deleção da região subtelomérica no braço longo do cromossoma 14, em ambos os kits e, posteriormente, a técnica de FISH comprovou essa deleção. Após estudos familiares, concluiu-se que dois dos irmãos apresentavam anomalias cromossómicas distintas do caso índex, envolvendo igualmente o cromossoma 14. Apesar de não ser possível efetuar o cariótipo à mãe (falecida), presume-se que estas alterações tenham tido origem numa anomalia cromossómica materna, uma vez que o pai deste indivíduo apresentava um cariótipo normal. Conclusões – Os autores apresentam os resultados citogenéticos dos vários indivíduos estudados, e realçam a raridade da existência de três rearranjos diferentes (um deles aparentemente equilibrado e dois desequilibrados), envolvendo o cromossoma 14, encontrados numa mesma família.