Browsing by Author "Serafim, Silvia"
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- A 1.77 Mb deletion in 3p26.3 encompassing CNTN6 and CNTN4 genes: case reportPublication . Brito, Filomena; Marques, Bárbara; Pedro, Sónia; Serafim, Silvia; Gonçalves, Rui; Freixo, João; Correia, HildebertoChromosome microarray analysis is a powerful diagnostic tool and is being used as a first-line approach to detect chromosome imbalances associated with intellectual disability, dysmorphic features and congenital abnormalities. This test enables the identification of new copy number variants (CNVs) and their association with new microdeletion/microduplication syndromes in patients previously without diagnosis. We report the case of a 7 year-old female with moderate intellectual disability, severe speech delay and auto and hetero aggressivity with a previous 45,XX,der(13;14)mat karyotype performed at a younger age. Affymetrix CytoScan 750K chromosome microarray analysis was performed detecting a 1.77 Mb deletion at 3p26.3, encompassing 2 OMIM genes, CNTN6 and CNTN4. These genes play an important role in the formation, maintenance, and plasticity of functional neuronal networks. Deletions or mutations in CNTN4 gene have been implicated in intellectual disability and learning disabilities. Disruptions or deletions in the CNTN6 gene have been associated with development delay and other neurodevelopmental disorders. The haploinsufficiency of these genes has been suggested to participate to the typical clinical features of 3p deletion syndrome. Nevertheless inheritance from a healthy parent has been reported, suggesting incomplete penetrance and variable phenotype for this CNV. We compare our patient with other similar reported cases, adding additional value to the phenotype-genotype correlation of deletions in this region.
- 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.
- Anomalias cromossómicas: síndromes e estratégias de diagnósticoPublication . Correia, Hildeberto; Brito, Filomena; Serafim, SilviaObjetivo: Divulgar a atividade da Unidade de Citogenética (UCI) do Departamento de Genética Humana do Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA): 1. Anomalias Cromossómicas e metodologias laboratoriais; 2. Síndromes/indicações clínicas e estratégias de diagnóstico; 3. Teste genético de array; 4. Apresentação de casos clínicos.
- CMA em diagnóstico pré-natal – “And so the story goes…”Publication . Serafim, Silvia
- Estratégias no Diagnóstico Pré-Natal (DPN)Publication . Serafim, Silvia; Correia, HildebertoTestes de rastreio e de diagnóstico em DPN: Testes usados durante a gravidez para determinar se um feto pode ser afetado por uma doença genética.
- 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.
- Rastreio Pré-natal / Diagnóstico Pré-natalPublication . Correia, Hildeberto; Serafim, Silvia; Marques, BárbaraRastreio pré-natal e diagnóstico pré-natal no ãmbito de anomalias cromóssomicas
- RPS6KA3 duplication in a male child with severe intellectual disabilityPublication . Serafim, Silvia; Marques, Bárbara; Ferreira, Cristina; Brito, Filomena; Silva, Marisa; Simão, Laurentino; Alves, Cristina; Pedro, Sónia; Sá, Joaquim; Correia, HildebertoRare inherited and de novo copy number variations (CNVs) are the cause of a variety of genetic disorders with intellectual disability (ID). Chromosomal microarray analysis (CMA) has been a rapid method to identify both large and small pathogenic genomic imbalances causing those disorders. The identification and classification of a CNV as pathogenic is not always easy to establish. If for deletions, or loss of function of specific genes, the likelihood of being causal is higher, for duplications, or overexpression for the same genes, the correlation is harder. Here we present a male child with severe ID and a family history with a female sibling presenting mild ID. Affymetrix Cytoscan HD CMA identified a gain of 530 Kb on Xp22.12 (chrX: 20016145_20546410 [GRCh37])) encompassing EIF1AX and RPS6KA3 genes. Inheritance was not yet possible to assess. Mutations in the RPS6KA3 gene causes Coffin-Lowry syndrome, a mental retardation syndrome with dysmorphic facial features and skeletal anomalies. X-linked mental retardation-19 is a nonsyndromic form of mild to moderate ID also caused by mutations in RPS6KA3. Carrier females may be mildly affected. This shows some phenotypic variability for the loss of function of this gene. Recently both familial and isolated cases have been reported with a duplication of the entire RPS6KA3 gene associated with mild to moderate ID. Those few cases suggest the increased dosage of this gene may be the cause for the ID in these patients and point to additional heterogenicity of genotype-phenotype of imbalances in this gene. The collection of more cases with duplication of RPS6KA3, as the one described herein, will help establish a better classification for those CNVs, finding the real burden on the patient’s phenotype, and delineating the subsequent genetic counseling for their families.
- Small Deletion of 143 Kb Encompassing Exon 2 of the AUTS2: Rise of a NewMicrodeletion Syndrome?Publication . Serafim, Silvia; Marques, Barbara; Filomena, Brito; Pedro, Sónia; Ferreira, Cristina; Ventura, Catarina; Gaspar, Isabel; Correia, HildebertoChromosome microarray analysis is a powerful diagnostic tool and is being used as a first-line approach to detect chromosome imbalances associated with intellectual disability, dysmorphic features and congenital anomalies. This test enables the identification of new copy number variants (CNVs) and their association with new microdeletion/microduplication syndromes in patients previously without diagnosis. Here we report the case of a 17 year-old female with severe intellectual disability, absence of speech, microcephaly and congenital abnormalities with a previous normal karyotype performed at a younger age. Affymetrix CytoScan HD chromosome microarray analysis was performed detecting a 143 Kb deletion at the 7q11.22 breakpoint, encompassing exon 2 of AUTS2 gene: arr[hg19] 7q11.22(69238957- 69381975)×1. The AUTS2 gene has been recently implicated in neurodevelopment and is a candidate gene for numerous neurological disorders. Common clinical features described in patients with deletions in AUTS2 gene include intellectual disability, speech delay and microcephaly, among others. Thus, the CNV identified in our patient explains the phenotype observed. We compare our patient with other similar reported cases, adding additional value to the phenotypegenotype correlation of deletions in this region. The growing collection of new cases with similar phenotypes, and the observation of this deletion occurring frequently de novo, indicates this CNV as a possible new single gene microdeletion syndrome.