Browsing by Author "Viegas, M."
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- 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.
- 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.
- Interstitial deletion on chromosome 14q in prenatal diagnosisPublication . Simão, L.; Alves, C.; Marques, B.; Pedro, S.; Ferreira, C.; Viegas, M.; Ventura, C.; Furtado, J.; Cruz, J.; Martins, A.; Cohen, A.; Fernandes, R.; Freixo, J.; Correia, J.; Correia, H.A limited number of prenatal diagnosis (PND) cases have reported interstitial deletions of the long arm of chromosome 14 involving the 14q31-32 region. Those cases presented cardiac anomalies, urogenital anomalies, congenital diaphragmatic hernia, and mild pyelectasis. We report the PND of a 33-year-old pregnant woman, who underwent chorionic villus sampling at 12 weeks of gestation after a positive combined 1st trimester screen. The karyotype revealed a 14q interstitial deletion. Amniocentesis was performed at 18 weeks of gestation to confirm the deletion and to exclude a confined placental mosaicism and a microarray analysis was performed in order to accurately define the deletion breakpoints. Cytogenetics analysis revealed a karyotype 46,XY,del(14)(q31q32.2)dn. Microarray analysis allowed to redefined the breakpoints accurate localization and the identification of a ~21Mb deletion (arr[hg19] 14q31.1q32.31(79917376_101568230)x1). At 18 weeks of gestation the fetus presented abnormal fetal biometric parameters (occipitofrontal diameter, cephalic perimeter and abdominal circumference) on ultrasound. After counseling the couple opted for pregnancy termination. The postmorten analysis presented decreased biometry, low weight and low fetal size, facial dysmorphism, clinodactyly, club foot, overlapping fingers and short penis. In internal habitus he presented thymus hypoplasia, bladder hypoplasia, and horseshoe kidneys. The genotype-phenotype correlation in PND pure del(14q) cases is not well established. Furthermore, to our knowledge, del(14q) had not been reported so early in the gestation yet. In this case the positive 1st trimester screen was related to the inverted ductus venosus and low PAPP-A value. The urogenital anomalies (as horseshoe kidneys) and biometry anomalies are described in the literature. However, to our knowledge, some features of the present case were not seen in other reported cases, for instance clinodactyly, club foot, overlapping fingers, thymus hypoplasia and bladder hypoplasia. Other reports described cardiac and cerebral anomalies, diaphragmatic hernia, and also UPD(14)like phenotypes, which are possibly liked to the 14q32 imprinted region. The establishment of a phenotype-genotype correlation is difficult given the size of the deletion, which includes a large number of genes in distinct regions. Nevertheless, this work contributes to a better identification of additional features associated to del(14q) that can be present in PND.
- Multiple non contiguous copy gains and a terminal loss in 8q24 identified in a fetus with cleft palate and lipPublication . Serafim, S.; Pedro, S.; Marques, B.; Tarelho, A.R.; Ferreira, C.; Simao, L.; Viegas, M.; Silva, M.; Alves, C.; Mourinha, V.; Ferreira, A.; Correia, H.Objectives: Chromosomal microarray analysis (CMA) is the recommended genetic test in pregnancies with ultrasound abnormalities but in some cases karyotype may still be needed to clarify the underlying mechanism of complex rearrangements. Here we report the case of a fetus from a healthy 24-year-old G1P0 woman, with a low risk for common aneuploidies in the 1st trimester prenatal screening but referred for CMA at 17+6 weeks of gestation due to cleft palate and lip in the 1st trimester ultrasound. Method: After a normal result in the rapid aneuploidy diagnostic test we performed CMA using ThermoFisher Cytoscan™ 750K. Our reporting resolution includes gains and losses larger than 35 Kb, considered clinically relevant for the course of the pregnancy. In this case further tests were done to assess recurrence risk and a possible chromosomal rearrangement: CMA and karyotype on the parents and karyotype on the fetus. Results: The CMA profile revealed a female fetus with three non-contiguous interstitial copy gains and a terminal loss in the long arm of chromosome 8 (8q24), as follows: - x4 copy gain at 8q24.12q24.13 with 585 Kb - x2 copy neutral region with 1.5 Mb - x4 copy gain at 8q24.13 with 2.9 Mb - x2 copy neutral region with 1.2 Mb - x3 copy gain at 8q24.21q24.23 with 17.8 Mb - x1 terminal loss at 8q24.3 with 130 Kb The fetal karyotype showed, in one of the chromosomes 8, an abnormal pattern in the long arm with a larger relative size. After parental studies the reported copy number variants were shown to be de novo. Conclusions. Most of the cases reported in the literature with gains along 8q result from a rearrangement involving another chromosome making it challenging to assess a genotype-phenotype correlation (PMID: 34265769; PMID: 31141803; PMID: 34794751). The few cases of individuals reported with isolated gains in the 8q24 have been described as having different features, depending on the size of the gain, and those may include facial dysmorphysms, clef lip and palate, developmental delay, among others (PMID: 25506438; PMID: 11484205; PMID: 33316910; UNIQUE - rarechromo.org: duplications of 8q). Recently a fetus with multiple congenital abnormalities, including clef palate, was reported having a similar imbalance, and although the parents decided to keep the pregnancy the baby died soon after birth given the extension of the congenital abnormalities (PMID: 30638476). The CMA results in our case explained the clef palate and lip identified in the fetus and, after genetic counseling, the parents opted to terminate the pregnancy. Although the identified non-contiguous gains and the terminal loss may suggest a mechanism of chromothripsis/chromoanagenesis for the arising of this abnormal chromosome 8, no further studies were performed after determining that the parents had a normal result and therefore a low recurrence risk for future pregnancies.
- Prenatal diagnosis of 7q11.23 duplication in a fetus with renal pelvic dilatation and the postnatal outcomePublication . Serafim, S.; Ferreira, C.; Simão, L.; 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.7q11.23 duplication syndrome is a multisystemic developmental disorder characterized by variable manifestations, such as speech delay, mild craniofacial anomalies with distinctive facial features, and intellectual ability ranging from mental retardation to normal cognitive development. Approximately 30% of individuals with 7q11.23 duplication have one or more congenital anomalies. Penetrance is complete with variable expression of phenotypic features. Prevalence has been estimated at 1:7,500-1:20,000. The 7q11.23 duplication is frequently inherited from a parent. Here we report a 33-year-old woman referred for prenatal diagnosis at 29 weeks of gestation due to fetal renal pelvic dilatation. Chromosomal microarray analysis (CMA) was performed after a normal molecular rapid aneuploidy test result and identified a 1.44 Mb duplication at 7q11.23 - arr [GRCh37] 7q11.23 (72,700,467-74,136,633)x3 - overlapping the 7q11.23 duplication syndrome region, in a female fetus. The gain was inherited from the mother which had no previous clinical evaluation but a later reassessment revealed mild cognitive delay and language impairment. Delivery was at 35 weeks due to a maternal respiratory infection with acute pulmonary edema. Newborn resuscitation was required for neonatal respiratory depression with an Apgar score of 1'-2, 5'-4, 10 '-8. Birth weight and length was 2140g and 43cm respectively, with a head circumference of 32cm. In the neonatal period a transient systolic murmur was identified with no alterations on the echocardiogram. Renal and bladder ultrasound showed pelvic dilatation with no changes of the ureteral tract, suggesting a relation with ureteropelvic junction syndrome. Left pyeloplasty for the ureteropelvic junction syndrome was performed at 14 months of age. Clinical evaluation at the age of 22 months revealed psychomotor development delay with delayed speech, facial features overlapping Williams-Beuren syndrome, and the systolic murmur grade I/VI was still present. Growth and weight were both normal. To the best of our knowledge this is the second prenatal case of 7q11.23 duplication described. Although genitourinary tract abnormalities are not the most common feature in patients with 7q11.23 duplication, congenital anomalies of the urinary tract can occur in 15%-18%, including hydronephrosis and unilateral renal agenesis. This shows that the ultrasound abnormalities not always suggest a specific syndrome but after the identification of a pathogenic CNV made possible by the use of CMA a correlation may be achievable. Additionally the discovery of CNVs in prenatal CMA may go beyond the context of the current pregnancy allowing for the identification of carriers thus having a larger impact in a family's health management and genetic counseling.
- Prenatal diagnosis of mosaic ring chromosome 16 - a rare event with uncertain prognosisPublication . Brito, F.; M. Silv, M.; Alves, C.; Ferreira, C.; Serafim, S.; Simão, L.; Marques, B.; Pedro, S.; Tarelho, A.; Furtado, J.; Lopes, P.; Silva, N.; Viegas, M.; Fernandes, A.; Teixeira, F.; Gomes, S.; Correia, H.Ring chromosomes are rare cytogenetic findings (prenatal frequency ~ 0.0075%) often associated with an abnormal phenotype, depending of the chromosomal origin, genetic content and the presence of a mosaic. Supernumerary ring chromosome 16 [r(16)] is rarely observed and mosaicism makes the genotype/phenotype correlation difficult. We report a de novo mosaic r(16) detected after prenatal diagnosis in a woman referred for advanced maternal age. Multiplex ligation-dependent probe amplification (MLPA) for aneuploidy testing of chromosomes 13, 18, 21 and X was normal. Karyotype was 47,XX,+r[10]/46,XX[15]. Chromosomal microarray analysis (CMA) on DNA obtained from long-term cultured amniocytes did not detect any alterations. MLPA with a pericentromeric probe kit on an uncultured sample showed a chromosome 16 gain, encompassing 16p11.2 and 16q11.2 regions, including TGFB1I1, AHSP, VPS35 and ORC6 genes, leading to partial characterization of the r(16). Although no phenotype has been correlated with overexpression of these genes, the 16p11.2 region is associated with neurodevelopmental disorders. Nevertheless individuals with microduplication of 16p11.2 and normal development have been described. The lack of a precise definition of genetic content of the r(16) and its mosaic form leads to uncertain prognosis of clinical outcome.