Browsing by Author "Antunes, Diana"
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- 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.
- 6q terminal deletion: a new contribution to genotype-phenotype correlationPublication . Simão, Laurentino; Marques, Bárbara; Sónia, Pedro; Antunes, Diana; Brito, Filomena; Silva, Neuza; Nunes, Luis; Correia, HildebertoDeletion of chromosome 6q is a relatively rare clinical entity associated to a considerable variability of the phenotypic spectrum. Mental retardation, facial dimorphisms, seizures, and brain abnormalities are typical features of this syndrome but until recently genotype-phenotype correlations have been scarce. We report a 15-year-old boy with slight developmental delay, intellectual disability, hypotonia, bilateral eye cataracts, mycrocephaly, agenesis of the corpus callosum, ventriculomegaly, paroxysmal attacks, kyphoscoliosis and trigonocephaly. Cytogenetic analysis revealed a de novo karyotype 46,XY,del(6)(q25.3). Microarrays genomic analysis with Cytoscan 750K allowed the refinement of the breakpoint region to 6q26q27, spanning approximately 7.76 Mb. The variation of the features attributed to 6q deletion syndrome is due primarily to differences in size and location of the segmental aneuploidy. Several studies suggest that deletions of 6q25 region can cause more severe anomalies that those including 6q26-27. Absence of IUGR, ear anomalies, ear loss, cleft palate, cardiac defects and genital hypoplasia in our patient are compatible with studies that generally correlate those features with deletions of 6q25 region. In addition, our patient presents retinal abnormalities, which has been associated to 6q26-q27 deletion. Some new candidate genes, localized at 6qter, have recently been described as being associated with some clinical features; an example is the candidate gene DLL1 and holoprosencephaly. Analysis of the breakpoints in most cases revealed a potential common breakpoint region at 8.0-9.0Mb from the chromosome 6q terminus where a fragile site exists (FRA6E). This suggests the breakage at the FRA6E may be the mechanism behind chromosome 6q subtelomeric deletions in some of the cases.Once the genotype-phenotype correlations have been scarce until now, with this study we aim to contribute to a better knowledge of the genotype-phenotype correlation of 6q terminal deletion and help to identify critical regions for several clinical features and developmental relevant genes.
- Espectro de alterações moleculares detetadas no gene CYP21A2 associadas a deficiência em 21 hidroxilasePublication . Gomes, Susana; Pereira-Caetano, Iris; Lopes, Maria Lurdes; Limbert, Catarina; Amaral, Daniela; Pina, Rosa; Antunes, Diana; Carvalho, Inês; Kay, Teresa; Sampaio, Lurdes; Pereira, Carla; Moldovan, Oana; Berta, Ana; Rebelo, Irene; Gaspar, Isabel; Cardoso, Helena; Rodrigues, José Cidade; Ramos, Lina; Ramos, Fabiana; Dinis, Isabel; Cardoso, Rita; Mirante, Alice; Gonçalves, JoãoA maioria dos doentes com hiperplasia suprarrenal congénita (HSC) apresenta alterações moleculares no gene CYP21A2, o qual codifica a enzima 21-hidroxilase (21-OH). Os doentes com a forma clássica de deficiência em 21-OH (21-OHD) apresentam a síntese de cortisol diminuída no córtex adrenal e, os casos mais graves, também apresentam deficiência de aldosterona. As mulheres com 21-OHD grave apresentam excesso de andrógenos desde a sua vida fetal conduzindo à virilização dos órgãos genitais externos. Tanto homens como mulheres com 21-OHD completa não sintetizam a aldosterona e, consequentemente, logo após o nascimento, podem desenvolver crises de perda de sal se não forem corretamente diagnosticados e tratados. A 21- OHD não clássica é devida à deficiência parcial em 21-OH, os fenótipos clínicos são menos graves, as mulheres não apresentam virilização dos genitais externos ao nascimento, e geralmente os sinais relativos a excesso de androgénios podem surgir durante a infância ou até mais tarde (durante ou após a puberdade). Neste trabalho descrevem-se as alterações e os genótipos mais frequentes encontrados em doentes portugueses não adultos com 21-OHD. As alterações mais frequentes encontradas na forma clássica da HSC são c.293-13C> G, diferentes deleções/quimeras/conversões génicas do gene CYP21A2 e c.518T> A, enquanto na 21-OHD não-clássica a variante c.844G> T é a mais frequente. Estes resultados contribuem para um diagnóstico correto e uma melhor gestão clínica dos doentes, para o seu aconselhamento genético e para oferecer o diagnóstico pré-natal a casais com risco de ter filhos afetados com a forma clássica de 21-OHD.
- Gestações gemelares: anomalias cromossómicas em diagnóstico pré-natal (2001-2012)Publication . Brito, Filomena; Simão, Laurentino; Alves, Ana; Silva, Marisa; Furtado, José; Ventura, Catarina; Ambrósio, Paula; Geraldes, Céu; Melo, Antonieta; Correia, Joaquim; Antunes, Diana; Caetano, Paula; Correia, HildebertoIntrodução: As gestações gemelares (GG) têm aumentado significativamente nos últimos anos, sendo este aumento atribuído a um efeito combinado de tratamentos de fertilidade e aumento da idade materna. As grávidas com GG têm um risco acrescido de anomalias cromossómicas fetais, comparativamente às de gestações simples. Objetivo: Avaliação dos resultados obtidos em estudos de Diagnóstico Pré-Natal (DPN) de Anomalias Cromossómicas em gestações gemelares, na Unidade de Citogenética (UCI) do Departamento de Genética Humana do Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, no período de Janeiro de 2001 a Junho de 2012. Material e Métodos: Analisaram-se retrospetivamente casos de GG que efetuaram DPN de anomalias cromossómicas no período considerado. Foram analisados os parâmetros: classificação da gestação, indicação clinica, idade materna, semanas de gestação e resultado do estudo citogenético. Resultados: Num total de 7792 amostras pré-natais analisadas foram consideradas 340, correspondendo a 172 GG. As indicações clínicas mais frequentes foram idade materna (89/172=51.7%) e alterações ecográficas em pelo menos um dos fetos (42/172=24.4%). A idade média das grávidas e do tempo de gestação foi de 34.3 anos e 17.7 semanas respetivamente. Foram detetados 8 cariotipos com alterações cromossómicas, correspondendo a 4.7% das GG. Nas gestações simples a taxa de anomalias cromossómicas observada foi de 5.3% (398/7452). Conclusão: A taxa de anomalias cromossómicas observada nas GG é inferior à observada nas gestações simples no mesmo período de tempo e tipo de amostragem, não correspondendo ao esperado. A taxa de anomalias cromossómicas detetada no total das gestações foi sobreponível aos valores reportados pela DGS.
- Hiperplasia congénita da supra-renal não clássica (hcsr-nc) por deficiência de 21-hidroxilase: avaliação clínica e aconselhamento genético de duas famílias portuguesasPublication . Matos, Lurdes Godinho; Antunes, Diana; Gomes, Susana; Pereira-Caetano, Iris; Gonçalves, João; Castelo Branco, Sara; Lopes, Lurdes; Kay, TeresaIntrodução: A hiperplasia congénita da supra renal surge por deficiência de 21-hidroxilase em 90-95% dos casos. É uma das doenças hereditárias de transmissão autossómica recessiva mais frequente. A gravidade da doença resulta do grau de deficiência enzimática da 21-hidroxilase, que depende da mutação que ocorre no gene CYP21A2. Pode ter duas apresentações clínicas: a forma clássica (perdedora de sal ou simplesmente virilizante) mais grave e a forma não clássica (ou expressão tardia) com bloqueio enzimático menos grave. Objetivos: Estudo de duas famílias portuguesas com HCSR-NC para melhor avaliação clínica e aconselhamento genético dessas famílias.
- Hyperprolinemia as a clue in the diagnosis of a patient with psychiatric manifestationsPublication . Duarte, Marco; Afonso, Joana; Moreira, Ana; Antunes, Diana; Ferreira, Cristina; Correia, Hildeberto; Sequeira, SilviaLately, microdeletions of the 22q region, responsible for DiGeorge syndrome or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorder. These manifestations seem to be related to certain genes located in the hemideleted region such as the proline dehydrogenase (PRODH) and the catechol-o-methyltransferase (COMT) genes. We describe a teenager who started his adolescent psychiatric care presenting cognitive impairment, irritable mood and aggressive behaviour with schizophrenia-like symptoms that scored 153 in the Positive and Negative Symptoms Scale (PANSS) assessment. Worsening of symptoms when the patient was treated with valproic acid, and plasma aminoacids showing an increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Mild dysmorphic features also suggested a possible 22q11 deletion syndrome that was confirmed. A mutation for Hyperprolinemia type I was also detected. Knowledge of the correct diagnosis was crucial for an adequate treatment.
- 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.
- Mucopolissacaridoses em população pediátrica: resultados de uma abordagem de precoce no âmbito do projeto FINDPublication . Gaspar, Paulo; Neiva, Raquel; Silva, Lisbeth; Diogo, Luísa; Ferreira, Ana Cristina; Miranda, Ana M.; Antunes, Diana; Louro, Pedro; Ribeiro, Sara; Oliveira, Sara; Garcia, Paula; Rodrigues, Esmeralda; Campos, Teresa; Silva, Carmen; Janeiro, Patricia; Sousa, Sérgio; Lopes, Altina; Nogueira, Célia; Pereira, Cristina; Alves, Sandra; Teles, Elisa Leão; Vilarinho, LauraAs Mucopolissacaridoses (MPSs), constituem um subgrupo das Doenças Lisossomais de Sobrecarga, causadas por deficiências em enzimas lisos somais, que catalisam a degradação dos glicosaminoglicanos. As MPSs têm apresentação multissistémica, heterogénea e consequentemente de diagnóstico difícil. O projeto FIND tem como objetivo alertar os clínicos para sinais e sintomas de risco ao mesmo tempo que disponibiliza uma ferramenta de diagnóstico. Este estudo pretende descrever uma abordagem desenvolvida no âmbito do projeto FIND para identificar doentes com mucopolissacaridoses (MPSs) em idade pediátrica, antes do aparecimento dos sintomas mais graves. A identificação atempada permitirá uma intervenção terapêutica precoce, assim como oferecer aconselhamento genético às famílias afetadas. O projeto FIND permitiu a identificação de 12 doentes de MPSs e a sua refe renciação para os respetivos centros de tratamento. Este estudo, para além da sua vertente educativa, coloca à disposição dos clínicos um ótimo meio para a identificação e caraterização de casos sinto máticos de MPS em idade pediátrica.
- Nonclassic Congenital Adrenal Hyperplasia (NCCAH) Due to 21-Hydroxylase Deficiency: Clinical Management and Genetic Counseling of Two Portuguese FamiliesPublication . Lurdes de Matos, Maria; Antunes, Diana; Gonçalves, João; Lopes, Lurdes; Kay, TeresaIntroduction: Congenital adrenal hyperplasia (CAH) due to 21-Hydroxylase deficiency occurs in 90-95% of cases, being a common autosomal recessive condition that can present with a wide range of hyperandrogenemic signs in childhood or adulthood. Severity of this disease is correlated with the enzymatic blockade of 21-Hydroxylase which depends of the mutation in gene CYP21A2. Two clinical forms are possible: classic, subdivided in salt-wasting and simple virilizing form (severe) and nonclassic or late onset (less severe). Aims: We studied two portuguese families with NCCAH due to 21-Hidroxilase deficiency in order to improve clinical management and genetic counseling of their members. Methods: Clinical presentation and hormonal assays (including test of tetracosactide) were performed in index cases (IC) . Genomic DNA of each family member was sequenced for the 9 most frequent mutations in CYP21A2. Total deletion of CYP21A , conversion in non functioning CYP21A1P or CYP21A1P_ CYP21A2 quimeras were also analyzed by enzymatic restriction. Results: Family 1- IC: Female, 31 years old with NCCAH diagnosed at age 6 , after investigation of precocious pubarche and with test of tetracosactide positive (17-alpha hydroxyprogesterone levels > 10-15 ng/ml) . Molecular study of CYP21A2 showed a mutation g.1683G> T , homozygous , in CYP21A2 and a non functioning allele of CYP21A2 , heterozygous (non severe 21-Hidroxilase deficiency). Mother was carrying a non functioning allele of CYP21A2 , heterozygous (severe); Father, Brother and Partner were heterozygous for mutation g.1683G> T (non severe). Family 2- IC: Female, 45 years old presenting hirsutism and oligoamenorrhea at age 35 and with test of tetracosactide positive confirming NCCAH Genetic study identified mutation g.1683G> T (less severe) in a copy and g.655A/C>G in another copy (splicing mutation severe). Familial genetic study identified two sisters (age 36 and age 40), asymptomatic but with pathologic genotype confirming NCCAH.
- The role of AKT3 copy number changes in brain abnormalities and neurodevelopmental disorders: four new cases and literature reviewPublication . Lopes, Fátima; Torres, Fátima; Soares, Gabriela; van Karnebeek, Clara D.; Martins, Cecília; Antunes, Diana; Silva, João; Muttucomaroe, Lauren; Botelho, Luís Filipe; Sousa, Susana; Rendeiro, Paula; Tavares, Purificação; Van Esch, Hilde; Rajcan-Separovic, Evica; Maciel, PatríciaMicrodeletions at 1q43-q44 have been described as resulting in a clinically recognizable phenotype of intellectual disability (ID), facial dysmorphisms and microcephaly (MIC). In contrast, the reciprocal microduplications of 1q43-q44 region have been less frequently reported and patients showed a variable phenotype, including macrocephaly. Reports of a large number of patients with copy number variations involving this region highlighted the AKT3 gene as a likely key player in head size anomalies. We report four novel patients with copy number variations in the 1q43-q44 region: one with a larger deletion (3.7Mb), two with smaller deletions affecting AKT3 and SDCCAG8 genes (0.16 and 0.18Mb) and one with a quadruplication (1Mb) that affects the entire AKT3 gene. All patients with deletions presented MIC without structural brain abnormalities, whereas the patient with quadruplication had macrocephaly, but his carrier father had normal head circumference. Our report also includes a comparison of phenotypes in cases with 1q43-q44 duplications to assist future genotype-phenotype correlations. Our observations implicate AKT3 as a contributor to ID/development delay (DD) and head size but raise doubts about its straightforward impact on the latter aspect of the phenotype in patients with 1q43-q44 deletion/duplication syndrome.