Browsing by Author "Ferreira, Cristina"
Now showing 1 - 10 of 31
Results Per Page
Sort Options
- 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.
- 16p13.11 microduplication: a case reportPublication . Marques, Bárbara; Ferreira, Cristina; Ventura, Catarina; Pedro, Sonia; Antunes, Diana; Nunes, Luis; Correia, HildebertoThe short arm of chromosome 16 is very rich in segmental duplications, predisposing this region of the genome to a number of recurrent rearrangements, namely deletions and duplications. Although it is already known that there is a strong association between 16p13.11 deletion and neuropsychiatric disorders, the clinical significance of its reciprocal duplication is not clearly defined yet. 16p13.11 microduplication that results of non-allelic homologous recombination is a very rare genetic alteration which can be associated with variable clinical features including behavioural abnormalities, developmental delay, congenital heart defects and skeletal anomalies. We report a 7-years-old boy with global developmental delay, speech absence, microcephaly, dysmorphic facial features and inexpressive facies. Microarray analysis revealed a 3.3Mb duplication comprising the 16p13.11- p12.3 region, which was confirmed by fluorescence in situ hybridization with a BAC clone for 16p13.11. Eight annotated genes are present in this region including NDE1, the candidate gene for neurological and behavioural phenotype. Although this microduplication has been found in the normal population, is significantly enriched in patients with autism, schizophrenia and cognitive impairment. Several case reports until now suggest that this genomic abnormality has incomplete penetrance and variable expressivity and can constitute a new syndrome. With this case we intend to contribute to expand the spectrum of clinical findings associated to this genomic abnormality and provide further knowledge of the pathogenic involvement of this duplication.
- A 669Kb deletion in 17q23.2, encompassing TBX2 and TBX4 genes, in a girl with a moderate developmental delay without any other pertinent abnormalityPublication . Ferreira, Cristina; Marques, Bárbara; Pedro, Sónia; Serafim, Silvia; Amorim, Marta; Correia, HildebertoMicrodeletion of the 17q23.1-q23.2 region recently emerged as a syndrome (OMIM#613355) based in a small number of cases with a common phenotype including mild-to-moderate developmental delay, heart defects, microcephaly, postnatal grow retardation, and hand, foot, and limb abnormalities. All patients reported to date present mild to moderate developmental delay, in particular speech delay, and half of them hearing loss. The smallest overlapping region has approximately 2.2 Mb and includes the transcription factors TBX2 and TBX4 genes. These genes have been implicated in a number of developmental pathways, including those of the heart and limbs. The TBX4 gene is also associated with the autosomal dominant small patella syndrome (SPS, OMIM 147891). Here we report a 8 year-old girl with moderate developmental delay including learning disabilities. The test for Fragile X syndrome indicated an allele within the grey area (number of repeats ~50 CGG) inherited from her mother and probably not relevant. Affymetrix Cytoscan HD chromosome microarray analysis was performed and a 669 Kb interstitial deletion was detected at 17q23.2 region, encompassing only five OMIM genes: BCAS3, TBX2, TBX4, NACA2 and BRIP1. To our knowledge this is the smallest deletion described in this region. None of the genes present in the deleted region are known to be associated with developmental problems. We compare our patient with the other similar reported cases, in order to add some increased value to the phenotype-genotype correlation of deletions in this region.
- 9q21.13q21.31 deletion in a patient with intellectual disability severe speech delay and and dysmorphic features a newly recognized microdeletion syndromePublication . Marques, Barbara; Serafim, Silvia; Pedro, Sonia; Tarelho, Ana Rita; Ferreira, Cristina; Gonçalves, Rui; Correia, HildebertoThe increased use of chromosomal microarray analysis has led to the identification of new microdeletion/microduplication syndromes, enabling better genotype-phenotype correlations. Interstitial deletions involving the long arm of chromosome 9 are rare but recently a microdeletion syndrome at 9q21.13 was suggested, with mental retardation, speech delay, epilepsy, autistic behaviour and moderate facial dysmorphism as the main characteristics. Here we present a male child with intellectual disability, severe speech delay, microcephaly and dysmorphic features carrying an interstitial deletion, detected by the Affymetrix Cytoscan HD microarray, of 6.56 Mb at 9q21.13q21.31 region encompassing 16 OMIM genes (arr[GRCh37] 9q21.13q21.31(76551542_83116342)x1). Among the genes in the deleted region the PRUNE2, PCSK5, RORB and TRPM6 genes are expressed in the nervous system and have been describe as being candidate genes to play a role in mental retardation or neurological disorders. Although the cohort of patients identified with deletions in this region is still small our patient phenotype partially overlaps the others described in the literature. The collection of more cases with deletion of the 9q21.13 region will help establishing a clear classification for this CNV, finding the real weight in the patient’s phenotype, delineating the genetic counseling for their families, and clearly establishing this microdeletion as a syndrome.
- 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
- cfDNA: que os fatores podem influenciar na opção pelo teste?Publication . Cruz, Jader; Carocha, Ana; Ferreira, Leonor; Rijo, Claudia; Ferreira, Cristina; Correia, Hildeberto; Cohen, AlvaroObjectivos: procurar fatores influenciadores na decisão das grávidas ao optar pelo teste de cffDNA após o RC.
- Characterization of a rare analphoid sSMC(7)Publication . Marques, B.; Brito, F.; Ferreira, Cristina; Correia, H.; Alves, C.; Amorim, A.; Pedro, S.
- Co-segregation of trichorhinophalangeal syndrome with a t(8;13)(q23.3;q21.31) familial translocation that appears to increase TRPS1 gene expressionPublication . David, Dezső; Marques, Bárbara; Ferreira, Cristina; Araújo, Carlos; Vieira, Luís; Soares, Gabriela; Dias, Cristina; Pinto, MaximinaTrichorhinophalangeal syndrome type I (TRPS I) is a rare autosomal dominant syndrome caused by haploinsufficiency of TRPS1 due to point mutations or deletions. Here we report the first familial TRPS I due to a t(8;13)(q23.3;q21.31) translocation breakpoint <100 kb from the 5’ end of TRPS1. Based on the additional abnormalities observed exclusively in the index patient that are mainly compatible with clinical features of TRPS, her phenotype was defined as expanded TRPS I including brain malformations and intellectual disability. Initial analyses did not reveal any genetic defect affecting TRPS1 or any genomic alteration within the breakpoint regions or elsewhere in the genome. The pathogenic chromosome 8q23.3 breakpoint is at position g.116,768,309_116,768,310 within a transposon type I element, 87 kb from the TRPS1 5’ end. The 13q21.31 breakpoint is within a tandem repeat region at position g.65,101,509_65,101,510 (genome assembly GRCh37/hg19). This breakpoint is flanked by protocadherin 9 (PCDH9) and protocadherin 20 (PCDH20). As an outcome of the translocation, an evolutionarily conserved non-coding VISTA enhancer element from 13q21.31 is placed within the TRPS1 5’ region, 1,294 bp from the breakpoint. The increased expression of TRPS1 found by three independent methods is most probably translocation allele derived and driven by the translocated enhancer element. The index patient’s expanded phenotype presumably involves the epithelial-to-mesenchymal transition pathway that may be due to TRPS1 overexpression. Together, these findings support that the reported translocation associated phenotypes are “cis-ruption” and TRPS1 overexpression related, the latter most probably caused by the novel enhancer element in the TRPS1 5’ region.
- 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.