Browsing by Author "Pedro, S."
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- 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.
- Characterization of a rare analphoid sSMC(7)Publication . Marques, B.; Brito, F.; Ferreira, Cristina; Correia, H.; Alves, C.; Amorim, A.; Pedro, S.
- Characterization of a rare analphoid supernumerary marker chromosome in mosaicPublication . Marques, B.; Alves, C.; Ferreira, C.; Correia, H.; Brito, F.; Pedro, S.; Amorim, M.Analphoid supernumerary marker chromosomes (SMCs) are a rare subclass of SMCs C-band-negative and devoid of alpha-satellite DNA. These marker chromosomes cannot be identified unambiguously by conventional banding techniques alone being necessary to apply molecular cytogenetic methods in favour of a detailed characterization. In this work we report an analphoid SMC involving the terminal long arm of chromosome 7, in 9 years-old boy with several 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. FISH analysis with alpha-satellite probes for all chromosomes, whole chromosome painting probe for chromosome 7, and D7S427 and TelVysion 7q probes, allowed establishing the origin of the SMC as an analphoidmarker resulting of an invdup rearrangement of 7q36-qter region. Affimetrix CytoScan HD microarray analysis, redefined the SMC to arr[hg19] 7q35(143696249-159119707)×2~3, which correspond to a gain of 15.42 Mb and encloses 67 OMIM genes, 16 of which are associated to disease. This result, combined with detailed clinical description, will provide an important means for better genotype-phenotype correlation and a more suitable genetic counselling to the patient and his parents, despite the additional difficulty resulting from being a mosaic (expression varies in different tissues). Analphoid SMCs derived from chromosome 7 are very rare, with only three cases reported so far. With this case we hope contribute to a better understanding of this type of chromosome rearrangements which are difficult for genetic counselling.
- Chromosomal disorders and male infertilityPublication . Simão, L.; Caetano, I.; Pedro, S.; Silva, M.; Ambrósio, P.; Gonçalves, J.; Brito, F.; Marques, B.; Alves, C.; Serafim, S.; Geraldes, M.C.; Correia, H.Male factor infertility is considered a complex disorder with a largely unknown etiology that affects about 7% of men. In general, genetic abnormalities account for 15%-30% of condition and Y chromosome microdeletions are also frequent. The study, based on our casuistic, aimed at contributing to a better understanding of the genetic causes of infertility. A group of 410 idiopathic infertile men with non-obstructive azoospermia, oligozoospermia, or unknown semen quality (based on clinical evaluation and/or sperm counts) was retrospectively selected. Conventional karyotype was performed in all samples; Y microdeletion screen was performed in 247 samples. Forty two abnormal karyotypes (10.2%) were found, indicating an elevated frequency of chromosome abnormalities among the selected infertile men, as compared to that of newborn populations (≈0.4%). This frequency is higher than that reported in most similar studies that pointed to frequencies ranging from 2.2%-14.3%. Klinefelter´s syndrome was the most common chromosome disorder (4.9%). There were 18 cases with 47,XXY karyotype and 2 cases of mosaicism involving lines 47,XXY and 46,XY. Reciprocal translocations were identified in 10 cases (2.4%), particularly in men with unknown semen quality. Overall, reciprocal translocations have been found in approximately 1% of the infertile men and more commonly in azoospermics than in oligozoospermics. However, this type of association was not found in the present study. On the other hand, Y microdeletions were identified in 16/247 cases (6.5%), more frequently in azoospermics (13.3%, corresponding to 8/60 azoospermics). Among these 8 cases, 7 presented deletions at the AZFc region. The marked presence of chromosomal abnormalities and Y microdeletions enphasizes the relevance of studying both factors in infertile men to improve genetic counseling, to allow the development of appropriate therapies, and to expand the knowledge about the ethiology of male infertility.
- Classification of the dup 15q13.3 CNV: A National data collectionPublication . Sousa, A.; Serafim, S.; Santos, R.; Custódio, S.; Ávila, M.; Dupont, J.; Dias P, P.; Moldovan, O.; Melo, J.; Ferreira, S.; Pires, L.; Leão, M.; Sá, S.; Prior, C.; Alves, C.; Barreta, A.; Tarelho, A.; Marques, B.; Pedro, S.; Lopes, F.; Maciel, P.; Correia, H.; Dória, S.; Rendeiro, P.; Castedo, S.; Carreira, I.; Sousa, A.B.Introduction: The proximal region 15q11q14 is one of the most unstable regions in the human genome, with six recognizable break points (BP1-BP6). In 15q13.3 there is a recurrent small CNV (BP4-BP5) consisting of a 350-680 Kb duplication, encompassing the CHRNA7 gene, which encodes the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor. Although microdeletions of CHRNA7 are known to cause intellectual disability and neuropsychiatric phenotypes with high penetrance, the patogenicity of CHRNA7 duplications remains unclear. Microduplication 15q13.3 seems to be associated with a phenotypic spectrum of cognitive impairment and neuropsychiatric/neurobehavioral disorders. However, the penetrance of this CNV is considered incomplete since it is present in clinically unaffected individuals in the general population and it is frequently inherited from apparently clinically normal parents. Nonetheless, some pedigree studies have found a history of neuropsychiatric problems among carrier family members. This study aimed at re-evaluating the dup 15q13.3 CNV in national laboratories. Materials and Methods: Our study collected data on 15q13.3 microduplications in eight Portuguese genetics laboratories, among subjects referred for microarray. Results: Here we present a total of seventeen cases with dup 15q13.3. The subjects had somewhat variable phenotypes, with a bias towards developmental delay and autism spectrum disorders. Inheritance was established for eight of the subjects, and the majority originated from the father. We had no access to clinical data on carrier parents. No de novo CNV was found. All laboratories involved classified this variant as of uncertain significance. Discussion/Conclusion: To better determine whether this CNV is benign or pathogenic, careful characterization of patient and control cohorts must be performed, including detailed patient phenotyping, inheritance, clinical evaluation of carrier parents, prevalence in controls, as well as genetic functional studies. We strongly support the creation of a national database for uncertain CNVs in order to clarify the relevance of these recurrent findings, allowing a definitive classification in either pathogenic or benign.
- Diagnóstico pré-natal tardio de uma gestação com anomalias ecográficas e com duplicação da região 7q11.23Publication . Simão, L.; Serafim, S.; Ferreira, C.; Alves, C.; Brito, F.; Silva, M.; Furtado, J.; Viegas, M.; Pedro, S.; Marques, B.; Rodrigues, M.; Sá, J.; Castro, M.J.; Mendes, P.; Vassal, H.; Correia, H.Introdução: O diagnóstico pré-natal (DPN) atempado de anomalias cromossómicas em fetos com anomalias ecográficas é fundamental no prognóstico da gravidez, ou na sua possível interrupção. Assim, a realização das ecografias fetais nas semanas preconizadas é determinante para a gestão dos casos anormais. Descrevemos um caso de uma gravidez mal vigiada, com ecografia fetal realizada às 29 semanas de gestação, onde se identificou uma dilatação pielo-calicial grave no rim esquerdo e dúvida na área cardíaca. Objectivos: Evidenciar que a vigilância atempada das gestações conjuntamente com a análise por microarray aumenta a capacidade de diagnóstico em gestações com anomalias fetais detetadas ecograficamente.
- Interstitial deletion on chromosome 14q in prenatal diagnosisPublication . Simão, L.; Alves, C.; Marques, B.; Pedro, S.; Ferreira, C.; Viegas, M.; Ventura, C.; Furtado, J.; Cruz, J.; Martins, A.; Cohen, A.; Fernandes, R.; Freixo, J.; Correia, J.; Correia, H.A limited number of prenatal diagnosis (PND) cases have reported interstitial deletions of the long arm of chromosome 14 involving the 14q31-32 region. Those cases presented cardiac anomalies, urogenital anomalies, congenital diaphragmatic hernia, and mild pyelectasis. We report the PND of a 33-year-old pregnant woman, who underwent chorionic villus sampling at 12 weeks of gestation after a positive combined 1st trimester screen. The karyotype revealed a 14q interstitial deletion. Amniocentesis was performed at 18 weeks of gestation to confirm the deletion and to exclude a confined placental mosaicism and a microarray analysis was performed in order to accurately define the deletion breakpoints. Cytogenetics analysis revealed a karyotype 46,XY,del(14)(q31q32.2)dn. Microarray analysis allowed to redefined the breakpoints accurate localization and the identification of a ~21Mb deletion (arr[hg19] 14q31.1q32.31(79917376_101568230)x1). At 18 weeks of gestation the fetus presented abnormal fetal biometric parameters (occipitofrontal diameter, cephalic perimeter and abdominal circumference) on ultrasound. After counseling the couple opted for pregnancy termination. The postmorten analysis presented decreased biometry, low weight and low fetal size, facial dysmorphism, clinodactyly, club foot, overlapping fingers and short penis. In internal habitus he presented thymus hypoplasia, bladder hypoplasia, and horseshoe kidneys. The genotype-phenotype correlation in PND pure del(14q) cases is not well established. Furthermore, to our knowledge, del(14q) had not been reported so early in the gestation yet. In this case the positive 1st trimester screen was related to the inverted ductus venosus and low PAPP-A value. The urogenital anomalies (as horseshoe kidneys) and biometry anomalies are described in the literature. However, to our knowledge, some features of the present case were not seen in other reported cases, for instance clinodactyly, club foot, overlapping fingers, thymus hypoplasia and bladder hypoplasia. Other reports described cardiac and cerebral anomalies, diaphragmatic hernia, and also UPD(14)like phenotypes, which are possibly liked to the 14q32 imprinted region. The establishment of a phenotype-genotype correlation is difficult given the size of the deletion, which includes a large number of genes in distinct regions. Nevertheless, this work contributes to a better identification of additional features associated to del(14q) that can be present in PND.
- Microarray in clinical practice – utility vs complexity. Mixed phenotype of duplication 15q11.2q13.1 and deletion 16p11.2Publication . Antunes, Diana; Rodrigues, M.I.; Carvalho, I.; Freixo, J.P.; Marques, B.; Pedro, S.; Kay, T.; Correia, H.; Castedo, S.; Nunes, L.Introduction: There’s a consensus to perform chromosomal microarray technique as first-tier clinical diagnostic test for individuals with developmental disabilities. However, given the complexity of clinical presentations, often several diagnostic methods are held before conducting microarray. Method: We report the case of a 5 year-old boy referred to Medical Genetics due to short stature, developmental disabilities and facial dysmorphic features. He was born from eutocic delivery after an uneventful pregnancy. He had psychomotor milestones delayed like sitting at 9 months and walking at 24 months, holding an immature broad-based gait. There was history of learning difficulties from both parents, and the mother has also short stature. On examination it was noted some facial dysmorphic features like high forehead, conical canines and rarefaction of the distal portion of the eyebrows. Due to the history of an episode of transient ataxia, and suspicion of an inherited metabolic disorder, he had already performed various analytical and imaging screenings, all normal. Results: Chromosomal microarray analysis revealed two pathogenic Copy Number Variants (CNV’s): 16p11.2 deletion and 15q11.2q13.1 duplication. The 15q11q13 microduplication syndrome (OMIM # 608636) is a very rare clinical entity with about 30 reported cases with maternal origin, and it is characterized by neurobehavioral disorder, hypotonia, cognitive impairment, epilepsy and short stature. The 16p11.2 microdeletion syndrome (OMIM # 613444) is also a rare clinical entity, with high penetrance, associated with obesity and developmental disabilities. Discussion: Despite the unquestionable utility of microarray, the correlation of the CNV's with the phenotype is often difficult by the rarity of these new microdeletion/duplication clinical entities. In this case the interpretation has increased difficulty because of the simultaneous existence of two distinct clinical entities. Segregation studies, which in the first step include parental analysis, are essential for genetic counseling and determining the risk of recurrence but also for a more accurate correlation genotype-phenotype.
- Mudanças no diagnóstico pré-natal cromossómico: indicações clínicas, amostras biológicas, metodologias e cromossomopatiasPublication . Simão, L.; Silva, M.; Alves, C.; Brito, F.; Serafim, S.; Ambrósio, P.; Geraldes, M.C.; Marques, B.; Ferreira, C.; Pedro, S.; Furtado, J.; Ventura, C.; Tristão, J.; Ferreira, A.; Correia, J.; Correia, H.Introdução: As mudanças no diagnóstico pré-natal de anomalias cromossómicas (DPN) nos últimos 10-15 anos foram contínuas e significativas. Objetivos: Propômo-nos analisar essa evolução: mudanças nas indicações clínicas; introdução das biópsias de vilosidades coriónicas (BVC); utilização do diagnóstico rápido de aneuploidias (DRA); estudos por microarray; alterações cromossómicas encontradas. Metodologia: Fez-se a avaliação retrospetiva nas gestações com amostras estudadas nos triénios 2004-2006 e 2014-2016. Analisaram-se os parâmetros indicação clínica, tipo de amostra, metodologias utilizadas e resultados. Resultados: Identificaram-se 68 fetos com cariotipo anormal em 2210 cariotipos (3,1%) em 2004-2006 e 208 fetos com cariotipo anormal em 2315 cariotipos (9,0%) em 2014-2016. A maior frequência de anomalias encontrou-se nos casos de rastreios ecográficos e combinados indicativos de risco acrescido de anomalia numérica e de progenitores portadores de alterações cromossómicas. As BVC permitiram respostas precoces nas gestações com anomalias numéricas e, adicionalmente, um aumento desses cariotipos (7.5% das amostras). O DRA permitiu ter uma resposta rápida nas anomalias numéricas mais frequentes (2 dias). As anomalias estruturais foram menos preponderantes nos cariotipos anormais (32,4% em 2004-2006 e 14.4% em 2014-2016). Discussão e conclusões: O DRA reduziu o tempo de resposta e das decisões sobre o futuro das gestações. O microarray permitiu identificar alterações sindromáticas em situações não resolúveis por outras metodologias. A utilização de BVC permite estabelecer uma melhor correlação fenotipo-genotipo em menores idades gestacionais. No entanto, as gestações com anomalias numéricas têm algum risco de perda fetal no primeiro e início do segundo trimestres. Assim, algumas BVC com cariotipos anormais resultariam em perdas espontâneas, o que poderia disponibilizar outros casos para DPN. Por outro lado, o menor número de anomalias estruturais equilibradas encontrado pode reduzir o conhecimento da variação genética nas famílias e na população. Um novo paradigma resulta da implementação dos testes não invasivos no DPN, para os quais ainda não conhecemos todas as limitações e repercussões.
- Multiple non contiguous copy gains and a terminal loss in 8q24 identified in a fetus with cleft palate and lipPublication . Serafim, S.; Pedro, S.; Marques, B.; Tarelho, A.R.; Ferreira, C.; Simao, L.; Viegas, M.; Silva, M.; Alves, C.; Mourinha, V.; Ferreira, A.; Correia, H.Objectives: Chromosomal microarray analysis (CMA) is the recommended genetic test in pregnancies with ultrasound abnormalities but in some cases karyotype may still be needed to clarify the underlying mechanism of complex rearrangements. Here we report the case of a fetus from a healthy 24-year-old G1P0 woman, with a low risk for common aneuploidies in the 1st trimester prenatal screening but referred for CMA at 17+6 weeks of gestation due to cleft palate and lip in the 1st trimester ultrasound. Method: After a normal result in the rapid aneuploidy diagnostic test we performed CMA using ThermoFisher Cytoscan™ 750K. Our reporting resolution includes gains and losses larger than 35 Kb, considered clinically relevant for the course of the pregnancy. In this case further tests were done to assess recurrence risk and a possible chromosomal rearrangement: CMA and karyotype on the parents and karyotype on the fetus. Results: The CMA profile revealed a female fetus with three non-contiguous interstitial copy gains and a terminal loss in the long arm of chromosome 8 (8q24), as follows: - x4 copy gain at 8q24.12q24.13 with 585 Kb - x2 copy neutral region with 1.5 Mb - x4 copy gain at 8q24.13 with 2.9 Mb - x2 copy neutral region with 1.2 Mb - x3 copy gain at 8q24.21q24.23 with 17.8 Mb - x1 terminal loss at 8q24.3 with 130 Kb The fetal karyotype showed, in one of the chromosomes 8, an abnormal pattern in the long arm with a larger relative size. After parental studies the reported copy number variants were shown to be de novo. Conclusions. Most of the cases reported in the literature with gains along 8q result from a rearrangement involving another chromosome making it challenging to assess a genotype-phenotype correlation (PMID: 34265769; PMID: 31141803; PMID: 34794751). The few cases of individuals reported with isolated gains in the 8q24 have been described as having different features, depending on the size of the gain, and those may include facial dysmorphysms, clef lip and palate, developmental delay, among others (PMID: 25506438; PMID: 11484205; PMID: 33316910; UNIQUE - rarechromo.org: duplications of 8q). Recently a fetus with multiple congenital abnormalities, including clef palate, was reported having a similar imbalance, and although the parents decided to keep the pregnancy the baby died soon after birth given the extension of the congenital abnormalities (PMID: 30638476). The CMA results in our case explained the clef palate and lip identified in the fetus and, after genetic counseling, the parents opted to terminate the pregnancy. Although the identified non-contiguous gains and the terminal loss may suggest a mechanism of chromothripsis/chromoanagenesis for the arising of this abnormal chromosome 8, no further studies were performed after determining that the parents had a normal result and therefore a low recurrence risk for future pregnancies.