DGH - Posters/abstracts em congressos internacionais
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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.
- 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.
- 2-DIGE of Red Blood Cells from Sickle-Cell Disease Patients with Severe Vaso-Occlusion.Publication . Vaz, Fátima; Charro, Nuno; Morais, Anabela; Lavinha, João; Penque, Deborah
- 3-Methylcrotonylglycinuria: a new common mutation in the Portuguese population?Publication . Fonseca, Helena; Sousa, Carmen; Marcão, Ana; Rocha, Hugo; Lopes, Lurdes; Vilarinho, LauraIntroduction: 3-Methylcrotonylglycinuria (MCG) is an inborn error of the leucine catabolism resulting from isolated biotin-insensitive deficiency of 3-methylcrotonyl-CoA carboxylase (3-MCC), the enzyme converting 3-methylcrotonoyl-CoA to 3-methylglutaconyl-CoA. The metabolic phenotype characterizing MCC deficiency is the elevated excretion of the diagnostic compounds 3-methylcrotonylglycine and 3-hydroxyisovaleric acid, and the presence of abnormally elevated blood levels of 3-hydroxyisovalerylcarnitine (C5-OH), as determined by tandem mass spectrometry (MS/MS). Expanded newborn screening for inborn errors of metabolism using MS/MS has demonstrated that 3-MCC deficiency is one of the most commonly detected inherited organic acidurias. Patient and methods: The authors report the results of molecular studies performed in six cases in a universe of thirty patients with an increase of C5-OH in the acylcarnitine profile. Blood spot samples from newborns are collected between day 3 and 6 in Watman 903 filter paper. Acylcarnitines in samples are analysed in tandem mass spectrometer. The molecular characterization is the study of genes MCCA and MCCB that encodes the enzyme 3-MCC. Results: The six cases showed the same novel mutation p.N230D in the MCCB gene, proving that this is the most common new mutation in our population. According to the studies conducted to this new mutation using bioinformatic applications, it is considered a benign mutation, but the alignment of species and the population study conducted, showed that this mutation is responsible for the biochemical phenotype found in these cases. Discussion: Of the thirty MCC cases studied, p.N230D mutation revealed to be the most frequent new mutation. Bioinformatic analysis showed that this mutation is located in a non conserved area but the mutant residue was never present in the homologous proteins analyzed.
- 47,XY,+del(X)(q21.31)/46,XY mosaicism in prenatal diagnosis - case report of a rare eventPublication . Ferreira, C.; Tarelho, A.; Marques, B.; Serafim, S.; Pedro, S.; Ferreira, A.; Correia, H.OBJECTIVES: Aneuploidies involving the sex chromosomes are the most common anomalies in humans. In many cases these anomalies are present in mosaic and may involve either the whole chromosome or just part of it. These anomalies constitute a challenge in prenatal diagnosis because it is generally very difficult to establish a reliable genotype-phenotype correlation. Here we report a rare event of a mosaic in which one cell line carries an additional abnormal X chromosome, with a terminal deletion at q21.31 region, and a normal XY constitution in the majority of the cells. METHODS: A healthy 36-year-old G1P1 woman was referred for prenatal diagnosis at 11+5 weeks of gestation for increased nuchal translucency. Chorionic villus biopsy was performed and molecular rapid aneuploidy result indicated an anomalous situation for the X chromosome in a male fetus. As the material was not sufficient to establish a culture an amniocentesis was performed at 17+3 weeks and karyotyping and microarray were performed in order to characterize the anomalous result. RESULTS: The results obtained indicated the presence of a mosaic involving an extra X chromosome with a terminal deletion, [47,XY,+del(Xq)/46,XY.arr[GRCh37] Xp22.33q21.31(169921_89283237)x1~2], which is compatible with a Klinefelter syndrome variant. CONCLUSIONS: Pregnancies affected by X chromosome aneuploidies diagnosed prenatally are at an increased risk of adverse fetal and neonatal outcomes. High quality information is critical for informed decision-making in pregnancy following a prenatal diagnosis of sex chromosome aneuploidy. The participant shall be able to understand the importance of breakpoints definition and the impact that a mosaicism situation have in prenatal diagnosis.
- 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
- ABC system used as an add-on to clarify germline variants previously classified as VUS according to ACMG guidelinesPublication . Rodrigues, Pedro; Theisen, Patrícia; Silva, Catarina; Mendonça, Joana; Carpinteiro, Dina; Vieira, Luís; Gonçalves, JoãoThe increasing number of patients screened by NGS to identify germline variants associated with hereditary breast/ovarian cancer (HBOC) syndromes, is leading to a growing number of variants classified as Variants of Uncertain Significance (VUS) according to ACMG guidelines1. Since the ACMG system merges functional and clinical data into a one-dimensional system, it is not always clear how the classification was obtained. The ABC system (ABCs) of variant classification2 splits functional and clinical grading and aims to give a better guide to variant significance. The main goals of this work were i) to apply the ABCs to a group of previously classified ACMG-VUS and ii) to evaluate the potential clinical impact of this review/classification. Germline variants (36 - 29 missense, 1 synonymous and 6 intronic) detected in 5 genes (BRCA1, BRCA2, ATM, CHEK2, PALB2) previously classified as ACMG-VUS, were selected from our database of patients with HBOC, to be reclassified with the ABCs. Variant assessment included: query of clinical and population databases, literature and in silico tools (VEP, HSF, Alamut, Varsome). Eleven variants were classified as Class 0 (functional - fVUS); 17 as class E (functional - HFE (Hypothetical Function Effect), and 8 as Class D (functional - LFE (Likely Functional Effect). fVUS are not clinically graded. Considering that ACMG-VUS are not actionable, it is still an ongoing debate if they should be reported or not. Since the ACMG merges functional and clinical data, it might be difficult for clinicians to understand how VUS classification is achieved. The ABCs allowed us to distinguish between VUS classified due to lack of data from those that might have a functional impact. Class 0 variants (11) should not be reported and class E (17) reporting is optional. The use of ABCs highlighted 8 variants (class D) which might be a susceptibility factor with functional impact and should be reported. Functional and segregation studies are of major importance to clarify the clinical significance of these variants. 1-PMID: 25741868. 2-PMID: 33981013. Support: FCT/MCTES, ToxOmics and Human Health (UIDB/00009/2020). GenomePT(POCI-01-0145-FEDER-022184).