Browsing by Author "Correia, H."
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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.
- Anemia de Fanconi – Estudo retrospetivo num período 34 anosPublication . Ambrósio, A.P.; Silva, N.; Viegas, M.; Silva, M-C.; Ventura, C.; Correia, H.Introdução: A Anemia de Fanconi (AF) é uma doença rara, com uma frequência estimada de 1 a 5 per 1.000.000 de nascimentos, podendo este valor aumentar se for considerado um grupo étnico com consanguinidade. É uma doença autossómica recessiva, que poderá ter uma transmissão ligada ao cromossoma X. Doentes com AF podem apresentar malformações congénitas, falência da medula óssea (que se carateriza por pancitopénia), hipersensibilidade a agentes clastogénicos, fragilidade cromossómica e uma maior suscetibilidade para doenças oncológicas. Devido à grande complexidade desta patologia a primeira abordagem de diagnóstico, consiste na deteção de aberrações cromossómicas (quebras, rearranjos estruturais, radiais, anéis) em células de sangue periférico em cultura com um agente clastogénico como o diepoxibutano (DEB) ou mitomicina C (MMC). Objetivo: Neste trabalho pretende-se apresentar os resultados dos estudos de instabilidade cromossómica induzida por DEB e MMC efetuados na nossa instituição. Métodos: Foi realizada a análise de uma série retrospetiva de 34 anos (1980-2014) de 243 amostras enviadas ao laboratório citogenética com suspeita de AF e de 28 amostras de familiares de doentes com AF. No total, foram analisadas 260 amostras de sangue periférico, 6 de biópsia de pele, 3 de líquido amniótico, 1 de sangue do cordão e 1 de sangue medular. As amostras foram processadas segundo o protocolo estabelecido para a análise cromossómica de doenças associadas a fraturas, incluindo cultura celular com estimulação por MMC e/ou DED, para cada produto biológico, seguida de análise microscópica com determinação da instabilidade cromossómica induzida pelo DEB, de acordo com o protocolo estabelecido pelo International Fanconi Anemia Registry (IFAR). Resultados: Nas 243 amostras analisadas, foram identificados 37 casos com AF. Nos estudos citogenéticos dos familiares com AF foram identificados mais 2 casos positivos para AF. Foram ainda observados, em 4 amostras de suspeita de AF, cariotipos anormais. Conclusão: Neste trabalho foram identificados 39 novos casos com AF, oriundos maioritariamente da região de Lisboa e Vale do Tejo e alguns casos pontuais da região autónoma dos Açores, região centro e dos países africanos de língua oficial portuguesa (PALOP). Este estudo evidência que a maioria dos casos apresentados se encontra subdiagnosticado. Estes resultados não permitem estimar uma frequência de doentes com AF em Portugal, uma vez que não engloba indivíduos de todas as regiões portuguesas, por outro lado estão incluídos dois indivíduos de origem PALOP. É necessário estabelecer um registo nacional de doentes com AF, para se poder calcular a frequência desta patologia no nosso país.
- 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.
- Deleção cromossómica intersticial em 14q “de novo”: apresentação de um casoPublication . Ribeiro, M.C.; Mota Freitas, M.; Ribeiro, J.; Lopes, M.M.; Oliva Teles, N.; Correia, H.; Fonseca e Silva, M.L.Introdução: As deleções intersticiais são anomalias cromossómicas estruturais, desequilibradas, resultantes de dois pontos de quebra, frequentemente associadas a quadros clínicos anormais devido à perda de material genético ativo (eucromatina). As consequências fenotípicas dependem do segmento cromossómico perdido e do número de genes aí localizados. Material e Métodos: Os autores apresentam o caso de um indivíduo do sexo masculino, de 11 anos de idade, referenciado para estudo citogenético por apresentar um quadro clínico de atraso de desenvolvimento psicomotor, défice cognitivo e problemas de comportamento. Realizaram-se culturas sincronizadas de linfócitos de sangue periférico, bandas GTG de alta resolução e, posteriormente, estudos de hibridação in situ por fluorescência (FISH) com sondas de pintura cromossómica total e subtelomérica, específicas para o cromossoma 14. Resultados: A análise das metafases revelou a presença de uma anomalia estrutural no cromossoma 14, interpretada como uma deleção intersticial do segmento compreendido entre as bandas 14q24.3 e 14q32.1. A análise por FISH permitiu confirmar esta deleção intersticial. Como os cariótipos dos pais foram normais, conclui-se que esta anomalia cromossómica é “de novo”, estabelecendo-se o cariótipo do doente como: 46,XY,del(14)(q24.3q32.1).ish del(14)(wcp 14+,SHGC36156+)dn Discussão: A deleção intersticial encontrada no cromossoma 14 implica uma monossomia do segmento 14q24.3→14q32.1. As alterações descritas mais comuns, associadas a esta deleção, incluem ADPM e algumas malformações minor. Os autores apresentam este caso pela raridade da anomalia citogenética encontrada e comparam-no com a literatura atual.
- Derivative chromosome 7 in a newborn with hypotelorism, cleft palate, agenesis of corpus callosum and semilobar holoprosencephalyPublication . Simão, L.; Serafim, S.; Brito, F.; Ventura, C.; Scortenschi, E.; Santos, V.; Correia, H.Cytogenetically visible unbalanced chromosome rearrangements involving the euchromatic regions most often result in severe phenotypic features. Often, it is not possible at microscopic level to distinguish if a chromosomal anomaly involves one or more than one chromosome. In these cases, the parents study is fundamental and is usually the first line of study. We report a female newborn with multiple anomalies. Ultrasonography at 32+6 weeks of gestation revealed moderate ventricular dilatation, microcephaly and intrauterine growth restriction (IUGR). Delivery was at 35 weeks and microcephaly, hypotelorism, complete medium cleft palate with nasal depression, agenesis of the corpus callosum, thalamic fusion and fusion of the lateral ventricles in the frontal region suggestive of semilobar holoprosencephaly (HPE) was observed. Seizures and nistagmus were described since the eighth day. Hypotonia was present. In addition, diabetes insipidus was diagnosed. Sepsis was developed at day 14 followed by death at day 18 in consequence of seizures and respiratory insuficiency. Cytogenetic analysis revealed an abnormal chromosome 7qter as a result of an unbalanced segregation of a maternal reciprocal translocation t(7;19), with breakpoints at 7q36.1 and 19q13.42. The newborn karyotype is 46,XX,der(7)t(7;19)(q36.1;q13.42)mat. The patient presented a partial trisomy of the region 19q13.42→qter and a partial monosomy of the region 7q36.1→7qter. Partial monosomy of chromosome 7qter has been characterized by a wide phenotypic manifestations, but HPE, microcephaly, midface hypoplasia, maxillary anomalies and sacral agenesis are frequently described. However, is not often reported in newborns. Partial trisomy 19q is a rare and severe condition, and has been described associated with low birth weight, growth retardation, microcephaly, seizures, dysmorphic facial features, short neck, clynodactyly, heart malformations, anomalies of the genitor-urinary and gastrointestinal tract. To our knowledge, there is only one previous case of der(7)t(7q;19q)(q36.1;q13.43) described, in a fetus who presented severe sacral agenesis and IUGR. The case herein reported presents some of the most common features of 7q36 partial monosomy and 19q terminal trisomy, although some of them are present in both conditions. The presence of those two imbalances may complicate the final phenotype but the important matter will be the counseling of the couple and to prevent future imbalances in their offspring.
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