Browsing by Author "Serafim, Sílvia"
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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.
- CNVs em loci de suscetibilidade com penetrância incompleta: da certeza no diagnóstico à incerteza no prognósticoPublication . Serafim, Sílvia; Marques, Bárbara; Correia, HildebertoO teste genético de array é a primeira linha no diagnóstico genético pós- -natal de situações como défice cognitivo, autismo e anomalias congénitas. Em pré-natal, este teste está indicado em gravidezes com anomalias ecográficas. Comparativamente ao cariotipo possibilita um aumento no diagnóstico entre 10-20% em pós-natal e 5-10% em prénatal. No entanto, também identifica alterações associadas a fenótipos variáveis, com penetrância incompleta (CNVs-LS), conferindo aumento da suscetibilidade a doenças do neuro-desenvolvimento, mas com prognóstico incer to. Neste estudo pretendemos definir um conjunto de CNVs-LS e a sua penetrância, estimada com dados da literatura, aferindo a sua ocorrência na coor te com teste genético de array realizado no INSA-DG-UCI. Definiram-se 21 CNVs-LS e dum total de 835 diagnósticos em pós-natal e 317 em pré-natal, identificaram-se 36 casos pós-natal e 11 em pré-natal, correspondendo a 4,3% e 3,5% do total, respetivamente. A penetrância estimada para as CNVs-LS apresenta variabilidade inter-publicações, e inter-fenótipo na população estudada, embora seja concordante para algumas variantes. Aferir a penetrância por variante é uma tarefa complexa e a análise por teste genético de array acarreta ainda incer tezas no diagnóstico e aconselhamento genético, dificuldades apenas superadas com o decorrer do tempo, estudo de mais coor tes e conhecimento das interações genótipo- -ambiente-fenótipo.
- 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.
- Is Nuchal Translucency of 3.0-3.4 mm an Indication for cfDNA Testing or Microarray? - A Multicenter Retrospective Clinical Cohort StudyPublication . Rybak-Krzyszkowska, Magda; Madetko-Talowska, Anna; Szewczyk, Katarzyna; Bik-Multanowski, Mirosław; Sakowicz, Agata; Stejskal, David; Trková, Marie; Smetanová, Dagmar; Serafim, Sílvia; Correia, Hildeberto; Nevado, Julian; Angeles Mori, Maria; Mansilla, Elena; Rutkowska, Lena; Kucińska, Agata; Gach, Agnieszka; Huras, Hubert; Kołak, Magdalena; Srebniak, Malgorzata IlonaIntroduction: This study aimed to evaluate the occurrence of clinically relevant (sub)microscopic chromosomal aberrations in fetuses with the nuchal translucency (NT) range from 3.0 to 3.4 mm, which would be potentially missed by cfDNA testing. Methods: A retrospective data analysis of 271 fetuses with NT between 3.0 and 3.4 mm and increased first trimester combined test (CT) risk in five cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed. Results: A chromosomal aberration was identified in 18.8% fetuses (1:5; 51/271). In 15% (41/271) of cases, trisomy 21, 18, or 13 were found. In 0.7% (2/271) of cases, sex chromosome aneuploidy was found. In 1.1% (3/271) of cases, CNV >10 Mb was detected, which would potentially also be detected by genome-wide cfDNA testing. The residual risk for missing a submicroscopic chromosome aberration in the presented cohorts is 1.8% (1:54; 5/271). Conclusion: Our results indicate that a significant number of fetuses with increased CT risk and presenting NT of 3.0-3.4 mm carry a clinically relevant chromosomal abnormality other than common trisomy. Invasive testing should be offered, and counseling on NIPT should include the test limitations that may result in NIPT false-negative results in a substantial percentage of fetuses.
- 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.
- Newborn whit a derivative chromosome X and ambiguous genitaliaPublication . Simão, Laurentino; Serafim, Sílvia; Brito, Filomena; Alves, Cristina; Silva, Marisa; Peliano, Ricardo; Ferreira, Cristina; Marques, Bárbara; Pedro, Sónia; Oliveira, Juliana; Branco, Tiago; Correia, HildebertoTranslocations involving the short arms of the X and Y in human chromosomes are uncommon. One of the primary functions of the X and Y chromosomes is gender phenotype determination. Here we report a newborn female with ambiguous genitalia and abnormal X chromosome. Karyotype was performed using the standard methods and Fluorescence in situ hybridization (FISH) directed for the SRY gene was used for confirmation of the clinical and cytogenetic suspicion. Chromosomal microarray analysis (CMA) was performed using CytoScan HD (Affimetrix®) to identified gains/loses on the der(X) chromosome. The analyse revealed one abnormal X chromosome in a female karyotype. Considering the ambiguous genitalia clinical information the abnormal X was considered to be compatible with a translocation X/Y. This was confirmed by the presence of signal for the SRY using FISH. CMA allowed to clarify a loss of 12.34 Mb at Xp22.33p22.2 and a gain of 7.41 Mb at Yp11.31p11.2 (ISCN = arr[GRCh37] Xp22.33p22.2(2703632_15050955)x1,Yp11.31p11.2(2650140_10059230)x1). The X deleted region includes several OMIM morbid genes, including CLCN4. Mutations in CLCN4 are associated with intellectual disability and impaired language development, and heterozygous females can be as severely affected as male. The gain on the Y encompasses nine OMIM genes, including the SRY gene, involved in the sexual male development. This additional information can be of great value for the child development. Translocations of segments of Y chromosome containing SRY are described in sexual reversion and true hermafroditism cases, which could explain the reason for referral for the newborn. Nevertheless, translocations between the X/Y chromosomes in females are expected to have a skewed inativation pattern in favour of the abnormal X and X-inativation studies could prove this likelihood. If a normal developmental of the child is observed over time this will be likely due to the preferable inativation of the abnormal X. Presently the child is about 1-year-old and she presents normal uterus, ovarian, and external genitalia, with absence of male gonads. No other clinical features have been identified.
- Novas Estratégias no Diagnóstico Pré-Natal (DPN)Publication . Serafim, Sílvia; Correia, HildebertoEnquadramento: Testes de rastreio e de diagnóstico em DPN: Testes usados durante a gravidez para determinar se um feto pode ser afetado por uma doença genética DPN permite permite: Tomada de decisão da gestação (por ex. IMG) ou Preparar estratégias específicas para o nascimento de um RN afetado.
- Prenatal diagnosis of Beckwith Wiedemann syndrome: a case reportPublication . Ferreira, Cristina; Tarelho, Ana; Marques, Bárbara; Serafim, Sílvia; Pedro, Sónia; Granja, Carla; Mata, Rodrigo; Martins, Ana Teresa; Carvalho, Inês; Correia, HildebertoBeckwith-Wiedemann syndrome (BWS) is the most common overgrowth disease. Phenotypically and genetically heterogeneous, it is linked with epigenetic/genetic aberrations on 11p15.4p15.5 chromosome region and the majority of cases are diagnosed after birth with prenatal diagnosis being difficult and depending on the identification of specific ultrasound (US) anomalies. Here we present a case of a fetus from a healthy 21-year-old primiparous woman, with a low risk in the first trimester aneuploidy screening and bilaterally increase in renal volume detected in the second trimester US. An amniotic fluid (AF) sample was collected at 24 weeks. Rapid aneuploidy diagnosis by QF-PCR and sequencing of a multigene panel for renal dysplasia were performed with a normal result for common aneuploidies and detection of a variant with uncertain significance, respectively. The pregnant was referred to a differentiated prenatal diagnosis center and a detailed US at 30 weeks and 3 days showed multiple features suggestive of BWS: macroglossia, weight estimation at P100, significantly enlarged kidneys without corticomedullary differentiation, hepatomegaly, prenasal and cervical subcutaneous thickening, and suspected cardiomegaly without structural heart disease. The methylation pattern study of 11p15 region by MS-MLPA revealed hypermethylation of H19/GF2: IG differentially methylated region (DMR), confirming the Beckwith-Wiedemann diagnosis. In contrast to postnatal cases that can be diagnosed by phenotypic scoring, prenatal diagnosis of BWS is relatively challenging because some common features cannot be detected by US and other features appear only after 30 weeks of gestation and may be missed on second-trimester morphological ultrasound. Omphalocele is the most common prenatal phenotypic BWS-associated feature, and is the first and most easily identified in prenatal screening, but there are other features that may suggest BWS such as macroglosia, macrosomia, placental mesenchymal dysplasia, polyhydramnios, and visceromegaly. Routine molecular testing of all fetuses with one or more prenatal BWS-associated features is of utmost importance, as early diagnosis is significantly beneficial for prenatal counselling, perinatal management allowing for better birth planning and postnatal care for neonatal hypoglycemia, respiratory distress, and risk of malignancy.
- Prenatal Diagnosis of Congenital Heart Disease IN A Fetus with A 8p23.1 Interstitial DeletionPublication . Simão, Laurentino; Marques, Bárbara; Serafim, Sílvia; Alves, Ana; Pedro, Sónia; Brito, Filomena; Ferreira, Cristina; Peliano, Ricardo; Silva, Marisa; Baptista, Teresa; Quintal, Idolinda; Tomás, Edite; Cascais, Inês; Correia, HildebertoIntroduction: Congenital heart disease (CHD) is the most common form of birth defects. The incidence of CHD is about 0.8% to 1% in live-born, full-term births, and it is ten times higher in preterm infants (8.3%). The atrioventricular septum defect (AVDS) is the most common CHD detectable in utero. AVSD is known to occur in either a nonsyndromic (isolated) form or, more commonly, as part of a malformation syndrome. Methodology: A 30-year-old woman at 12 weeks of gestation was referred for prenatal diagnosis due to fetal AVSD. Chromosomal microarray analysis (CMA) was carried out after a normal molecular rapid aneuploidy test result. Results: CMA identified, in a male fetus, a 3.11 Mb interstitial deletion at 8p23.1 - arr[GRCh37] 8p23.1(8824857_11935465)x1. This region encompasses 17 OMIM genes including GATA4. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function. Parental testing was requested and CMA was performed revealing that the deletion is de novo. Discussion: Deletions and mutations of the GATA4 gene are associated with cardiac septal defects. This deletion has a pathogenic clinical significance. The AVSD found in the fetus can be explained by the observed genomic change. Interstitial deletions of 8p23.1 are associated with a variable spectrum of anomalies that include congenital heart malformations. The prevalence is unknown but 8p23.1 deletions are rare. Most 8p deletions occurs de novo. The accuracy of cardiac defects in obstetric ultrasound and the identification of the genetic cause provide more knowledge for the genetic counseling. The parents opted to terminate the pregnancy.
- Restrição de crescimento fetal e cromossomopatias: 5 anos de resultados de DPN no INSAPublication . Simão, Laurentino; Serafim, Sílvia; Silva, Marisa; Ambrósio, Paula; Alves, Cristina; Geraldes, Maria Céu; Marques, Bárbara; Ferreira, Cristina; Pedro, Sónia; Tarelho, Ana Rita; Furtado, José; Cohen, Álvaro; Ferreira, Ângela; Mourinha, Vera; Brito, Filomena; Correia, HildebertoAs anomalias do crescimento fetal são uma importante causa de morbilidade e mortalidade perinatais. Os fatores envolvidos na restrição de crescimento fetal (RCF) podem ser maternos, placentários e fetais. Nos fatores fetais, as cromossomopatias estão descritas entre 6 e 32% dos fetos com RCF. Avaliar o tipo e significado das cromossomopatias, na etiologia da RCF, e do seu valor diagnóstico em pré-natal. Avaliar o impacto da introdução da metodologia de microarray no DPN por comparação com o cariotipo. Procedeu-se ao estudo retrospetivo das amostras recebidas, entre nov-2013 e nov-2018, com indicação clínica de RCF isolado ou associado a alterações ecográficas. O Diagnóstico Rápido de Aneuploidias (DRA) foi usado como teste inicial seguido por estudos por citogenética clássica ou por microarray. No período considerado recebemos 56 amostras com indicação de RCF, com idade gestacional entre as 11 e as 34 semanas. Em parte das amostras foi pedido DRA, estudo citogenético ou pesquisa de microdeleções e noutras foi pedido DRA e estudo por microarray. Foram identificadas 6 alterações cromossómicas em 31 casos com estudo citogenétco/pesquisa de microdeleções. Nos casos com microarray foram detetadas 5/25 alterações. Nos 11 (19,6% dos casos) fetos portadores de cromossomopatia, cinco apresentavam RCF isolado, ou associado a alterações do líquido amniótico, e os outros seis apresentavam RCF associada a outras malformações fetais, designadamente do foro cardíaco. As cromossomopatias identificadas nestes fetos incluíram trissomias 18, triploidias e ganhos/perdas de material genómico nos casos estudados por microarray. Nestes últimos, quatro alterações não seriam detetáveis por cariotipo, revelando o maior valor diagnóstico daquela metodologia. A triploidia é comum nos casos de RCF e constitui cerca de 27% das anomalias encontradas nesta coorte podendo, assim, a RCF ser considerada como bom marcador desta situação. Globalmente, a frequência de anomalias encontrada (cerca de 20%) revela a importância do diagnóstico genético em fetos com RCF.