Percorrer por autor "Alves, Cristina"
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- 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
- 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.
- Discordant Chromosome Placental Mosaicism in a Dichorionic Twin PregnancyPublication . Silva, Marisa; Caetano, Paula; Olival, Vanessa; Alves, Cristina; Simao, Laurentino; Ferreira, Cristina; Marques, Bárbara; Furtado, José; Ventura, Catarina; Soares, Sérgio; Correia, Hildeberto
- Early results of next-gen cytogenetics implementation in PortugalPublication . David, Dezső; Freixo, João; Marques, Bárbara; Carvalho, Inês; Tkachenko, Natália; Oliva-Teles, Natália; Marques, Mariana; Cardoso, Manuela; Fino, Joana; Alves, Cristina; Fortuna, Ana; Sófia, Dória; Pinto de Moura, Carla; Correia, Hildeberto; Marques Carreira, Isabel; Sá, Joaquim; Gonçalves, Rui Miguel; Lavinha, João; Kay, Teresa; Talkowski, Michael; Morton, CynthiaBackground: Most approaches are insensitive to the full mutational spectrum of chromosome rearrangements associated with human developmental abnormalities. Therefore, our aim is to introduce next-generation sequencing (NGS) into clinical cytogenetics, creating a sequence-based NextGen Cytogenetics to catalyze a dramatic advancement in clinical diagnostics. Methods: Twenty families with chromosome rearrangement-associated diseases, including two prenatal (PN) cases, have been enrolled. Fourteen of these were also analyzed by NGS using large-insert paired-end libraries. Results: The majority of these cases were confirmed to be balanced reciprocal rearrangements, whereas 4 were complex chromosomal rearrangements including 1 of chromothripsis. Thus far, over 50 breakpoints were identified disrupting protein coding genes, lncRNAs, or intergenic regions, thus revealing candidate genes or genomic loci. These cases are further assessed for pathogenicity from positional effects on genes located within topological domains (TADs) containing the breakpoints using DECIPHER predictions of haploinsufficiency. In one PN case, the 16q24 breakpoint disrupts ANKRD11, etiologic in the autosomal dominant KBG syndrome (OMIM #148050), predicting an abnormal phenotype. The chromothripsis case, submitted as 46,XY,t(7;14)(q22;q32.1),inv(15)(q21.2q26.1), proved by NGS to carry two further deletions, at 3p12 (5.3 Mb) and 15q14 (488 kb), as well as an insertion of 644.4 kb from 15q14 into 3p14. The inv(15) is in fact a complex rearrangement of 15q with eight breakpoints. Conclusions: We demonstrate that NGS-based chromosomal rearrangement characterization leads to major improvements in identification of chromosomal aberrations and in prediction of clinical outcomes of postnatally and prenatally detected genomic rearrangements, and to contributions to human genome annotation.
- Incidental X Linked Findings A female fetus with a gain in the DMD genePublication . Marques, Bárbara; Serafim, Silvia; Pedro, Sónia; Ferreira, Cristina; Simão, Laurentino; Alves, Cristina; Viegas, Mónica; Silva, Marisa; Brito, Filomena; Amorim, Marta; Correia, Joaquim; Correia, HildebertoIn prenatal diagnosis, chromosomal microarray analysis (CMA) has not yet fully replaced conventional cytogenetic but has rapidly become the recommended genetic test in pregnancies with ultrasound abnormalities. This methodology allows the identification of pathogenic small copy number variation (CNVs) in 5-10% of pregnancies with ultrasound abnormalities and a normal karyotype, increasing the diagnostic yield. However, this increased resolution can also result in the detection of incidental findings. Here we report a fetus referred for prenatal diagnosis due to skeletal dysplasia. Affymetrix Cytoscan HD chromosome microarray analysis was performed and a 204 kb gain was detected at Xp21.1 region (chrX: 31993622_32191110 [GRCh37]) in a female fetus, encompassing the intron 44 of the DMD gene, for the largest gene transcript. Nevertheless, if we considered the smaller transcripts it encompasses exon 1. The gain was maternally inherited. The DMD gene is involved on Becker muscular dystrophy, Cardiomyopathy, dilated, 3B and Duchenne muscular dystrophy. Intron 44 is a preferential breakpoint in about 30% of all DMD deletions, being the DMD transcript NM_004006.2 responsible for dystrophin expression in the skeletal muscle.The FGFR3 gene sequencing revealed the presence of the c.1118A >G, p.Y373C mutation associated to Thanatophoric Dysplasia, type 1 (TD1) justifying the ultrasound abnormalities.With this case, we reinforce that the discovery of CNVs in prenatal CMA goes beyond the correlation with the CNV and the ultrasound abnormalities. Incidental findings can also have a larger impact to the family clinical managing, even if not for the ongoing pregnancy for the reproductive future of the couple.
- Molecular characterization of a rare analphoid supernumerary marker chromosome derived from 7q35 → qter: a case reportPublication . Marques, Bárbara; Ferreira, Cristina; Brito, Filomena; Pedro, Sónia; Alves, Cristina; Lourenço, Teresa; Amorim, Marta; Correia, HildebertoBackground: Analphoid supernumerary marker chromosomes (aSMC) constitute one of the smallest groups of SMC, and are characterized by a centromeric constriction but no detectable alpha-satellite DNA. These marker chromosomes cannot be properly identified by conventional banding techniques alone, and molecular cytogenetic methods are necessary for a detailed characterization. Analphoid SMC derived from chromosome 7 are extremely rare, with only five cases reported so far. Case presentation: In this work we report an aSMC involving the terminal long arm of chromosome 7 in a 10-year-old boy with multiple 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. Next, we performed FISH analysis with multiple DNA probes and cCGH analysis. This identified the origin of the SMC as an analphoid marker resulting of invdup rearrangement of 7q35-qter region. Affimetrix CytoScan HD array analysis redefined the aSMC as a 15.42 Mb gain at 7q35-q36.3 (minimum tetraplicated region-chr7: 143,594,973-159,119,707; GRCh37/hg19) of maternal origin that encloses 67 OMIM genes, 16 of which associated to disease. Uniparental disomy of chromosome 7 (UPD 7) has been excluded. Conclusions: We report the first patient with an aSMC(7) derived from the terminal 7q region who has been molecularly and clinically full characterized. The use of SNParray in the characterization of SMC reveals to be a powerful tool, giving information not only about copy number variation but also about loss-of-heterozygosity and parental origin. We conclude that an integrated genome-wide copy number variation analysis, if possible associated to FISH and gene expression studies, could facilitate in the future the difficult task of establishing accurate genotype-phenotype correlations and help to improve genetic counselling.
- 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.
- A rare case of Beckwith–Wiedemann syndrome caused by a de novo microduplication at 11p15.5 of paternal originPublication . Ferreira, Cristina; Marques, Bárbara; Alves, Cristina; Barbosa, Mafalda; Fortuna, Ana; Reis-Lima, Margarida; Correia, HildebertoBeckwith–Wiedemann syndrome (BWS) is a disorder of growth regulation exhibiting somatic overgrowth and predisposition to paediatric tumours. With an incidence estimated at 1 in 13,700, it is caused by various epigenetic and/or genetic alterations associated with disturbances within two different 11p15 domains that are controlled by distinct imprinting control regions (ICR), ICR1 and ICR2. The majority of patients have abnormalities within ICR2 presenting hypomethylation, while less frequent aetiologies include mosaic paternal 11p uniparental disomy (11patUPD), maternally inherited mutations of the CDKN1C gene, and hypermethylation of ICR1. A few patients have cytogenetic abnormalities involving 11p15.5. Since the subgroups are associated with different recurrence risks, the identification of the molecular cause of BWS is particularly important for the follow-up of the patient and the genetic counselling of both the patient and the family. Here, we report a 13-year-old girl with clinical diagnosis of BWS presenting macrosomia, umbilical hernia, kidney abnormalities, hydramnius, prematurity, typical face, advanced bone age, moderate developmental delay, prominent occiput and forehead, round face, epicanthus, short nasal bridge, and microretrognathia. Cytogenetic analysis with highresolution banding showed an apparently normal karyotype. Microsatellite analysis and methylationspecific multiplex ligation-dependent probe amplification revealed a de novo microduplication at 11p15.5 of paternal origin. Duplication has a minimum size of 600 kb, covering only ICR1, not affecting ICR2. This sporadic case with a de novo duplication without other chromosomal abnormalities makes genotype–phenotype correlation difficult. As far as we know, this is one of the smallest duplications associated with BWS and is consistent with the independent regulation of ICR1 and ICR2. Our patient presented moderate developmental delay and craniofacial features typical of 11p15 duplication. Future studies exploiting this subtle 11p15.5 rearrangement will provide an important tool to further dissecting the genomics of BWS region and the pathogenesis of this imprinting disorder.
- A rare de novo unbalanced complex rearrangement involving chromosomes 12, 18 and 20 in a child with dysmorphic featuresPublication . Alves, Cristina; Marques, Bárbara; Brito, Filomena; Silva, Marisa; Rodrigues, Rosário; Duarte, Guida; Sousa, Ana Berta; Bicho, Anabela; Correia, HildebertoComplex chromosomal rearrangements (CCRs) are rare structural abnormalities that involve three or more breakpoints located on two or more chromosomes and are often associated with developmental delay, mental retardation and congenital anomalies. Here, we report the case of a rare de novo CCR in a girl who was 9 months old when first reported to us. At 15 months old, her clinical features included marked hypotonia, severe psychomotor delay, progressive postnatal microcephaly, strabismus, depressed nasal root, hands and feet malformations, heart defects, recurrent respiratory infections and bilateral hearing deficit still in study. Conventional cytogenetic analysis revealed an unbalanced complex rearrangement, involving chromosomes 12, 18 and 20, and an apparent loss of material of chromosome 18 resulting from an interstitial deletion. Further molecular cytogenetic studies were performed: whole chromosome painting probes for the involved chromosomes and chromosomal comparative genomic hybridization. These studies revealed that apparently no other chromosomes were involved and confirmed a del(18)(q21.1q22) of approximately 17 Mb on the derivative chromosome 18. The latter chromosome also had material from der(12) to der(20) in its constitution. As most CCRs involving chromosome 18q show rearrangements in the q21, some authors argue that this region might be a breakpoint “hotspot”. On the other hand, cases of single deletions on 18q are predominantly terminal. Interstitial deletions are much rarer, and to our knowledge, this is the first report of a CCR with a del(18)(q21.1q22). The phenotype of patients with deletions within this region, reported so far, seems very similar to the one of our patient, and this may contribute to a better understanding of the genotype–phenotype correlation in this type of structural abnormalities.