Browsing by Author "Simão, Laurentino"
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- 15q11.2q13.1 interstitial gain in a fetus with an increased risk for T21: When classification and clinical outcome are divergentPublication . Serafim, Sílvia; Pedro, Sónia; Marques, Bárbara; Tarelho, Ana; Viegas, Mónica; Simão, Laurentino; Ferreira, Cristina; Carvalho, Inês; Cohen, Álvaro; Correia, HildebertoIntroduction: Copy number variants (CNV) of the 15q11.2q13.1 region are associated to recurrent microdeletion/microduplication syndromes in which the phenotype is dependent on the parental origin of the CNV. We report the case of a fetus from a healthy 39-year-old G6P3A2 woman, with an increased risk for trisomy 21 in the 1st trimester prenatal screening. Chromosomal microarray analysis (CMA) was requested and revealed a pathogenic duplication in which the outcome was dependent of the parental origin of the affected allele. Methods: DNA was extracted from a chorionic villus sample and CMA was performed using Cytoscan™ 750K. Parental follow-up studies to assess the origin of the CNV were performed. Results: The CMA profile revealed a male fetus with a 4,89 Mb interstitial gain in 15q11.2q13.1. CMA of the parents showed that the duplication was paternally inherited. Discussion: The detected CNV is a recurrent known microduplication and according to the American College of Medical Genetics and Genomics guidelines is classified as pathogenic. However the phenotype is dependent on the parental origin of the duplication. When it arises in the maternally allele it has a severe outcome with hypotonia, cognitive deficit, seizures, among others. If the CNV occurs in the paternal allele although some patients might show developmental delays and behavioral disturbances most cases are rarely symptomatic. In this case, CMA of both parents showed that the CNV identified in the fetus was paternally inherited. Although the CMA result did not explained the increased risk for T21 after determining the duplication had been inherited from the father it allowed the prediction of the most likely resulting phenotype for the fetus as a milder or even asymptomatic. Follow-up ultrasounds at gestation age of 17w+6d and echocardiogram at 21w+3d showed no structural abnormalities. The baby was born at 37w+5d with an Apgar index of 10/10/10, with no dysmorphic features or malformations, and a normal physical exam. This case illustrates that although the use of genetic tools using artificial intelligence and following determined guidelines can be helpful for the purpose of consistency and standardization on the classification we always need careful evaluation from a clinical laboratory geneticist on the context of each case. Additionally it also shows how critical parental testing can be, not only to assess recurrence risk but to provide the best possible tool to ascertain the outcoming phenotype and allow the best choices to the couple after genetic counselling.
- 6q terminal deletion: a new contribution to genotype-phenotype correlationPublication . Simão, Laurentino; Marques, Bárbara; Sónia, Pedro; Antunes, Diana; Brito, Filomena; Silva, Neuza; Nunes, Luis; Correia, HildebertoDeletion of chromosome 6q is a relatively rare clinical entity associated to a considerable variability of the phenotypic spectrum. Mental retardation, facial dimorphisms, seizures, and brain abnormalities are typical features of this syndrome but until recently genotype-phenotype correlations have been scarce. We report a 15-year-old boy with slight developmental delay, intellectual disability, hypotonia, bilateral eye cataracts, mycrocephaly, agenesis of the corpus callosum, ventriculomegaly, paroxysmal attacks, kyphoscoliosis and trigonocephaly. Cytogenetic analysis revealed a de novo karyotype 46,XY,del(6)(q25.3). Microarrays genomic analysis with Cytoscan 750K allowed the refinement of the breakpoint region to 6q26q27, spanning approximately 7.76 Mb. The variation of the features attributed to 6q deletion syndrome is due primarily to differences in size and location of the segmental aneuploidy. Several studies suggest that deletions of 6q25 region can cause more severe anomalies that those including 6q26-27. Absence of IUGR, ear anomalies, ear loss, cleft palate, cardiac defects and genital hypoplasia in our patient are compatible with studies that generally correlate those features with deletions of 6q25 region. In addition, our patient presents retinal abnormalities, which has been associated to 6q26-q27 deletion. Some new candidate genes, localized at 6qter, have recently been described as being associated with some clinical features; an example is the candidate gene DLL1 and holoprosencephaly. Analysis of the breakpoints in most cases revealed a potential common breakpoint region at 8.0-9.0Mb from the chromosome 6q terminus where a fragile site exists (FRA6E). This suggests the breakage at the FRA6E may be the mechanism behind chromosome 6q subtelomeric deletions in some of the cases.Once the genotype-phenotype correlations have been scarce until now, with this study we aim to contribute to a better knowledge of the genotype-phenotype correlation of 6q terminal deletion and help to identify critical regions for several clinical features and developmental relevant genes.
- 9q34.3 microdeletion by MLPA in a fetus with cardiac defectsPublication . Marques, Bárbara; Ferreira, Cristina; Brito, Filomena; Alves, Cristina; Carvalho, Lucilia; Furtado, José; Ventura, Catarina; Silva, Marisa; Simão, Laurentino; Correia, Joaquim; Correia, Hildeberto
- À descoberta da Ciência - Conhecer e prevenir doenças genéticas: Contributo da Citogenética e da Genética molecularPublication . Simão, Laurentino; Gonçalves, JoãoResumo dos temas abordados no âmbito da Genética Molecular: - Epidemiologia e patologia molecular das hemoglobinopatias, fibrose quística, infertilidade masculina e hiperplasia supra-renal congénita - Diferentes mutações e suas consequências - Fundamentos moleculares de identificação de mutações na molécula de DNA/em genes de interesse - Identificação de casais em risco - Importância do aconselhamento genético - Diagnóstico pré-implantação e diagnóstico pré-natal Resumo dos temas abordados no âmbito da Citogenética: - Diagnóstico pré-natal e pós-natal de doenças cromossómicas - Do DNA aos cromossomas - Os cromossomas humanos - Incidência e importância das doenças cromossómicas - Tipos de doenças cromossómicas - Da citogenética clássica à citogenética molecular
- Citogenética convencional / CitogenómicaPublication . Simão, Laurentino; Marques, Bárbara; Correia, Hildeberto
- Citogenética e Diagnostico Pre-natalPublication . Simão, Laurentino
- A complex chromosomal rearrangement in a child with developmental delay, fractious behavior, and craniofacial anomalies, compatible with Smith-Magenis SyndromePublication . Simão, Laurentino; Alves, Cristina; Brito, Filomena; Marques, Bárbara; Ferreira, Cristina; Gaspar, Isabel; Dieudonne, V.; Cabral, P.; Meneses, I.; Duarte, Guida; Correia, HildebertoSmith-Magenis Syndrome (SMS) is a micro-deletion syndrome, and encompasses a picture of dysmorphology, mental defect, and fractious behavior. Evaluation of complex chromosome rearrangements (CCRs) and their potential phenotypic consequences is a common challenge in the genetics clinic and knowledge about the genotype/phenotype relationships are limited. We report the case of a 14-year-old boy who was referred by SMS, presenting developmental delay, fractious behavior, reduced sensitivity to pain, macrocranium and distinctive facial features. Following karyotyping, fluorescence in situ hybridization (FISH) using WCP probes for the chromosomes involved in CCR and 17p11.2 probe for SMS region was performed. Lately, chromosomal Comparative Genomic Hybridization (cCGH) and genomic microarray studies were also performed in order to identify genomic imbalances. The cytogenetic analysis revealed a karyotype: 46,XY,inv(3)(p23q27)t(3;10)(p13.2;p11.2),inv(14)(q13q32)dn.ish inv(3)t(3;10)(wcp10+), der(10)t(3;10)(wcp3+),inv(14)(wcp14+). Parental karyotypes were normal, although the father presented a marked cognitive delay. FISH analyses showed no deletion in 17p11.2 region and confirmed the cytogenetic results, namely the presence of CCR. Additionally, cCGH and genomic microarray studies did not reveal any gains/losses of genetic material in the breakpoints regions. Despite the clinical features of SMS, deletions or duplications in the SMS critical region were not detected in this patient. However, a small number of SMS present a mutation in the RAI1 gene instead of a 17p11.2 deletion, the former cause could not be excluded On the other hand, in CCRs de novo, an apparently balanced karyotype may be associated with an abnormal phenotype, including an increased risk of intellectual delay and congenital malformations. Further studies comprising, e.g., sequencing of the breakpoints, chromatin conformation analysis and refinement of the SMS critical region analysis might be useful to elucidate the phenotypic characteristics. However, the patient has been absent of routine clinical reevaluation; the etiology of the father’s cognitive delay could help shedding some light on the patient phenotypic features.
- Deleção intersticial 7q33q34 em fetos de gravidez gemelar monocoriónica diamnióticaPublication . Simão, Laurentino; Marques, Bárbara; Ferreira, Cristina; Serafim, Sílvia; Alves, Cristina; Silva, Marisa; Viegas, Mónica; Peliano, Ricardo; Brito, Filomena; Bernardeco, Joana; Cruz, Jader; Pedro, Sónia; Martins, Ana; Tarelho, Ana; Carvalho, Inês; Cohen, Álvaro; Correia, HildebertoIntrodução: O acompanhamento de gestações gemelares pode revelar-se desafiante se houver alterações ecográficas e discrepâncias entre os fetos. Deleções intersticiais 7q, abrangendo diferentes regiões e apresentando tamanho variável, são raras, e encontram-se quase exclusivamente descritas em pós-natal. Objectivos: Apresentamos o caso de uma gestante, de 32 anos, com gravidez gemelar monocoriónica e diamniótica de 16 semanas, referenciada por bolsas jugulares bilaterais, crescimento no P10-P20 e discrepância no pico sistólico de velocidade da artéria cerebral média (PSV-ACM). Foi efetuada colheita de liquido amniótico para estudo por microarray cromossómico (CMA). Metodologia: Foi efeituado diagnóstico rápido de aneuploidias (DRA) por QF-PCR (Devyser®), ao que se seguiu CMA com array CytoScan 750K (Thermo Fischer®) e cariótipo. Resultados: O DRA revelou um resultado normal. O CMA permitiu a identificação de uma deleção intersticial com 9,0 Mb em 7q33q34 - arr[GRCh37] 7q33q34(133411316_142427027)x1. A alteração engloba 12 genes mórbidos. O cariotipo confirmou o resultado: 46,XX,del(7)(q32.3q34)dn. Após aconselhamento genético, o casal optou por interrupção da gestação. Conclusões: Deleções intersticiais na região 7q32 a 7q35 apresentam grande variabilidade fenotípica. As características mais comuns são: atraso de desenvolvimento e da linguagem, défice intelectual, dismorfias faciais e atraso de crescimento. Nos raros casos descritos com alterações cromossómicas parcialmente sobreponíveis ao caso em estudo, a CNV tem sido classificada como patogénica. No único caso com referência ao período pré-natal e com alteração quase totalmente sobreponível, descreve-se decréscimo de movimentos fetais, baixo peso à nascença, atraso de desenvolvimento, défice intelectual, dismorfias faciais e infeções múltiplas. A alteração cromossómica encontrada poderá explicar a relativa restrição de crescimento fetal, não tendo as bolsas jugulares, presentes em ambos os fetos e a discrepância PSV-ACM sido até agora descritos. Gestações com alterações ecográficas e CNVs, mas com reduzida bibliografia, são desafiantes na interpretação dos resultados a nível laboratorial e clínico. Só a descrição de mais casos permitirá um ganho de conhecimento em saúde.
- Diagnosis and prevention of chromosomal disordersPublication . Simão, LaurentinoClinically significant chromosomal defects occur in 0.65% of all births, with high morbidity and mortality. Chromosome disorders form a major category of genetic disease. They account for a large proportion of all reproductive wastage, congenital malformations, and mental retardation and play an important role in the pathogenesis of malignancy. Specific chromosome abnormalities are responsible for more than 100 identifiable syndromes. The strategies followed in cytogenetics have changed over the past 25 years, moving from the exclusive use of classical cytogenetic methods (karyotyping) to the use of molecular biology methods (molecular cytogenetics and cytogenomics). The cytogenetic studies deserves a great attention since allows identifying the chromosomal abnormalities behind the congenital anomaly. This fact allows establishing genotype-phenotype relationships and the cause and prognosis of pathological pregnancies and population genetic diseases. The utility of studies in prenatal diagnosis (PND) and in patients with chromosomal disorders extends to the possibility of intervening in the diagnosis, prognosis and prevention of the genetic disease, as illustrated with the presentation of some case studies in the laboratory, that also assesses the value of new techniques implementation in a cytogenetic laboratory in order to obtain a complete result. In the other hand, the analysis of retrospective case series with an epidemiological approach contributes to the knowledge of the etiological cause of certain groups of chromosomal abnormality. For instance, Down Syndrome (DS) is the most common chromosomal disorder and the most common cause of moderate mental retardation. It is the most frequent abnormality in PND and is even one of the reasons for its implementation. We carried out a large study on the last 20000 PND we received in the laboratory. 2% showed karyotype compatible with DS. An increased number of karyotypes with DS were detected since chorionic villus sampling (CVS) started to be received in the laboratory. The implementation of rapid aneuploidy detection methods in PND also allowed a faster reporting time of trisomy 21. However, one question remains in discussion: pregnancies affected by DS have a great risk of spontaneous fetal loss during the first trimester and earlier second-trimester. Thus, some CVSs in DS cases will result in spontaneous miscarriages. These thematic show the role of chromosome abnormalities in the diagnosis and prevention of the genetic disease and also the complexity of the ways that we choose.
- Diagnóstico Pré-Natal de Anomalias CromossómicasPublication . Simão, Laurentino; Correia, HildebertoObjetivo: DPN – Diagnóstico, Prognóstico, Prevenção e Tratamento das anomalias cromossómicas fetais.
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