Background: The 22q11.2 deletion syndrome (22q11.2 DS) causes a wide variety of symptoms, but the central nervous system (CNS) dysfunction is the one most likely to affect the day-to-day life of those affected by this genetic disorder. In addition to affecting the educational needs of children with 22q11.2 DS, the neurological deficits in childhood and adolescence could be related to future psychosis and schizophrenia, which can affect 30% of these patients. Thus, the development of screening tools for CNS dysfunction could help identify children who are most at risk for developing later psychosis, allowing them to receive additional care. As saccadic eye movement behaviours reflect the integrity of multiple brain structures, a battery of oculomotor tasks could help identify neurological deficits. This study sought to test the hypothesis that children with 22q11.2 DS would have deficits in oculomotor performance compared to typically developing children. Methods: A cohort of 16 children with 22q11.2 DS, and 32 age- and sex-matched controls completed prosaccade, antisaccade, delayed memory-guided sequential (DMS) and predictive eye movement tasks. Results: Compared to controls, children with 22q11.2 DS exhibited increased direction errors in the antisaccade task, increased timing errors in the DMS task, as well as decreased predictive and increased regular saccades in the predictive task. The group of children with 22q11.2 DS also exhibited an increase in saccade amplitude in the prosaccade, antisaccade and predictive tasks, increased error in saccade trajectory in the prosaccade, antisaccade and DMS tasks and decreased saccade velocity in the predictive saccade tasks. Conclusion: This study showed that performance in the eye movement tasks could be used to assess injury to the frontostriatal circuitry and cerebellum in children with 22q11.2 DS. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-04-29 15:16:39.848

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Made available in DSpace on 2016-08-10T10:39:15Z (GMT). No. of bitstreams: 1 ANA JULIA DA CUNHA LEITE.pdf: 2339232 bytes, checksum: 9ce285061088b4ef8d6cdd81ece2961e (MD5) Previous issue date: 2016-03-14 / The chromosome 22q11.2 region has long been implicated in genomic diseases. Some genomic regions exhibit numerous low copy repeat with high identity in which provide increased genomic instability and mediate deletions and duplications in many disorders. DiGeorge Syndrome is the most common deletion syndrome and reciprocal duplications could be occurring in a half of the frequency of microdeletions. We described five patients with phenotypic variability that carries deletions or reciprocal duplications at 22q11.2 detected by Chromosomal Microarray Analysis. The CytoScan HD technology was used to detect changes in the genome copy number variation of patients who had clinical indication to global development delay and a normal karyotype. We observed in our study three microdeletions and two microduplications in 22q11.2 region with variable intervals contained known genes and unstudied transcripts as well as the LCRs that are often flanking and within this genomic rearrangement. The identification of these variant are of particular interest due to it may provide insight in genes or genomic regions there are crucial for specific phenotypic manifestations and are useful to assist the quest for understanding the mechanisms subjacent to genomic deletions and duplications. / A região do cromossoma 22q11.2 tem sido implicada em doenças genômicas. Algumas regiões genômicas exibem numerosas regiões de repetições de pequeno número de cópias que proporcionam o aumento da instabilidade genômica e mediam deleções e duplicações em muitas desordens. A Síndrome de DiGeorge é a síndrome de deleção mais comum e as duplicações recíprocas ocorrem na metade da frequência das microdeleções. Nós descrevemos cinco pacientes com variabilidade fenotípica que possuem deleções ou duplicações recíprocas em 22q11.2 detectados pela Análise Cromossômica por Microarray. A tecnologia CytoScan HD foi usada para detectar alterações da variação do número de cópias no genoma de pacientes que tiveram indicação clínica de atraso global no desenvolvimento com cariótipo normal. Observamos no nosso estudo três microdeleções e duas microduplicações na região 22q11.2 com intervalos variáveis onde contém genes conhecidos e transcrições não estudadas, tais como as LCRS que muitas vezes flanqueiam estes rearranjos genômicos. A identificação destas variantes são de particular interesse para fornecer uma visão dos genes ou das regiões genômicas que são cruciais para as manifestações fenotípicas específicas e são úteis para auxiliar na busca pela compreensão dos mecanismos subjacentes à deleções e duplicações genômicas.

22q11.2 deletion syndrome (22q), also known as Velocardiofacial Syndrome or DiGeorge Syndrome, is one of the most common genetic syndromes with an incidence of 1 in 2500 to 1 in 4000 (Wang et al., 2009). It is the most identified human chromosomal microdeletion syndrome to date (Wang et al., 2009). 22q is associated with a wide spectrum of clinical features including various palate, cardiac, and immunological abnormalities (Lynch et al., 1995; Wang et al., 2009). 22q is also the most common genetic cause of velopharyngeal dysfunction (VPD). Posterior cranial fossa (PCF) and cervical spine variations may influence velopharyngeal (VP) port closure. Although some studies have analyzed PCF size in individuals with 22q, there has not been extensive analysis of skull base anomalies and their correlation to velopharyngeal depth. The purpose of this study was to examine PCF measures and their effects on VP dimensions in children with 22q using a non-sedated imaging protocol. 34 participants, 17 with 22q and 17 with normal VP anatomy (age range: 4-12 years) completed the study. Participants were imaged using a 3D anatomical scan. MRIs were transferred into Amira 6.4 Visualization Volume Modeling software. Linear and angular measures were obtained in the sagittal image plane on the 3D MRI scans. Measures included: distance from the palatal plane to C1, pharyngeal depth, anterior cranial base angle, posterior cranial base angle, length of the clivus, McRae line and supraocciput of the PCF, angle of clivus, and the PCF angle formed by the McRae line and the supraocciput. It is hypothesized that shorter clivus length and smaller PCF angle between McRae line and supraocciput noted in individuals with 22q DS could be related to larger pharyngeal depth, which contributes to hypernasality typically seen in 22q. Results from this study indicate that children with 22q demonstrate larger pharyngeal depth, a more obtuse anterior cranial base angle (NSB angle), a more acute posterior cranial base angle (SBO angle), shorter length of the clivus, longer supraocciput length, and a more obtuse angle of clivus. The NSB angle was positively correlated with pharyngeal depth while the SBO angle was negatively correlated with pharyngeal depth. The angle of clivus was positively correlated with both pharyngeal depth and resonance severity.

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Orientadores: Vera Lúcia Gil da Silva Lopes, Iscia Teresinha Lopes Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T11:59:54Z (GMT). No. of bitstreams: 1 Monteiro_FabiolaPaoliMendes_M.pdf: 4745618 bytes, checksum: 220053db4f2a750f68c332b998074576 (MD5) Previous issue date: 2012 / Resumo: A deleção 22q11. 2 é a mais frequente deleção intersticial na espécie humana, ocorrendo em aproximadamente 1/4000 nascidos vivos. Esta pode manifestar-se através de amplo espectro fenotípico, já sendo descritas mais de 180 manifestações clínicas asociadas. Frequências da deleção variando de 0% a 75% têm sido encontradas em diferentes estudos dependendo da manifestação primária escolhida, bem como do desenho do estudo e critérios de inclusão utilizados. Muitos estudos foram realizados com o propósito de definir quais pacientes deveriam ser triados para a deleção 22q11.2 em populações com distintas manifestações da mesma, visando uma abordagem com maior custo-efetividade, porém ainda hoje um consenso não foi atingido e a questão ainda é debatida. Até o presente momento, não existem estudos direcionados a definir, de maneira objetiva, qual ou quais destes dismorfismos sugestivos têm maior relevância durante a avaliação dismorfológica de indivíduos com diferentes manifestações do espectro da deleção. Com o objetivo de contribuir na definição de critérios clínicos e dismorfológicos que possam otimizar a indicação da realização de exame confirmatório, foram investigados 194 pacientes divididos em quatro grupos clínicos - Suspeita de deleção com alterações palatais {Grupo 1), suspeita de deleção sem alterações palatais (Grupo 11), malformações cardíacas associadas ao espectro da deleção 22ql1.2 {Grupo III) e indivíduos com dignóstico de esquizofrenia {Grupo IV). Todos foram testados para a deleção 22q11.2 por meio da técnica de Multiplex Ligant-Probe Amplification (MLPA). Para cada grupo, um checklist específico, incluindo dismorfismos e outras características clínicas, foi desenvolvido e aplicado. Pacientes do Grupo IV foram examinados independentemente por dois geneticistas clínicos, a fim de definir a presença de dismorfismos relacionados às síndromes de deleção 22ql1.2 (22q11.2DS) e a concordância na indicação de testes confirmatórios. A deleção 22q11.2 foi detectada em 45 pacientes {23,2%), assim distribuídos: 35/101 {34;7%) do Grupo I, 4/18 (22,2%) do Grupo 11, 6/52 {11,5%) do Grupo III e em nenhum indivíduo do Grupo IV. A taxa de concordância entre os dois observadores para indicação de exame confirmatório para o Grupo IV foi de 91,3%. Os dados clínicos foram analisados por distribuição de frequência e estatisticamente em cada um dos grupos e subgrupos. Cada grupo clínico foi discutido de forma independente e seus resultados comparados àqueles previamente descritos por outros pesquisadores. Sinais clínicos entre indivíduos com deleção e sem deleção foram comparados, sendo signifcantes para a suspeição das 22q11.2DS: face alongada (p<0,001), pálpebras "hooded" (p=0,015), nariz típico (p=0,041), conformação tubular do nariz (p=0,046) e hipoplasia alar (p=0,012). Os resultados demonstram objetivamente que algumas características dismórficas têm maior probabilidade de estarem associadas à presença da deleção 22q11.2. Baseados nos resultados obtidos e na revisão da literatura, é proposta uma abordagem sistemática para triagem de pacientes com manifestações distintas do espectro da deleção 22q11.2, visando uma melhor relação de custo-efetividade / Abstract: The 22q11.2 deletion is the most frequent intersticial deletion in the human species, occurring in approximately 1/4000 live births. It is associated with a wide phenotypic spectrum, with over 180 clinical manifestations already described. Distinct approaches have detected frequencies of the deletion ranging from 0% to 75%, depending on the primary manifestation of the studied population and selection criteria. Many studies have been conducted to define which patients would be eligible for screening for the 22q11.2 deletion, though so far the issue is still up for debate. To the best of our knowledge, no study has been directed towards objectively defining which suggestive dysmorphisms are relevant while evaluating individuals with distinct manife.stations of the 22q11.2 deletion syndromes (22q11.2DS) . In order to contribute to the delineation of possible clinical and dysmorphologic guidelines and to optimize decision to proceed with confirmatory testing, 194 individuals were evaluated. Group I- clinical suspicion of 22q11.2DS with palatal anomalies, Group II -clinical suspicion without palatal anomalies, Group Ill -cardiac malformations associated with the 22q11.2DS and Group IV- schizophrenic patients. All of them were evaluated and tested for the 22q11.2 deletion using Multiplex ligation-dependent probe amplification (M LPA). Group-specific checklists were developed to collect dysmorphologic and clinical data. Also, patients from Group IV were examinated independently by two clinical geneticists, in order to define the presence of suggestive 22ql1.2DS dysmorphisms and concordance rate in indication to proceed with laboratorial investigation. The 22q11.2 deletion was detected in 45 patients (23.2%), distributed as such: Group I 35/101 (34.7%), Group 114/18 (22.2%), Group Ill 6/52 (11.5%) and none from Group IV. Concordance of clinical features and indication of confirmatory test in Group IV by two examiners was 91.3%. Clinical data was analyzed by frequency and statistical tests. Each group was independently discussed and the results compared to those previously described by other researchers. Several independent dysmorphisms were compared between individuals with and without the 22q11.2 deletion, and a long face (p<0.001), hooded eyelids (p=0.015), a tubular conformation (p=0.046) or other forms of typical nose (p=0.041), and alar hypoplasia (p=0.012) were statiscally more likely to be found in patients that tested positive for the deletion. Conclusions: The results objectively demonstrate that some dysmorphic features have a higher probability of being correlated to the presence of the 22q11.2DS. Based on these results and the review of the literature, a systematic approach for screening patients with distinct manifestations of the 22ql1.2DS in a more cost-effective way is proposed / Mestrado / Genetica Medica / Mestra em Ciências Médicas

Le syndrome de DiGeorge ou microdélétion 22q11.2, est la délétion chromosomique la plus fréquente chez les êtres humains. Cette délétion est liée à la recombinaison homologue non-allélique au cours de la méiose induisant la perte d’en moyenne 40 gènes. Les études de corrélation génotype/phénotype chez les patients ont révélé des différences phénotypiques entre individus et cela indépendamment de la taille des microdélétions. L’hypothèse de l’implication des mécanismes épigénétiques dans la variabilité phénotypique observée a été soulevée mais reste encore inexplorée. C’est dans ce contexte que nous nous intéressons à l’étude des mécanismes épigénétiques au cours du développement, dans cette pathologie à travers l’utilisation d’un modèle de cellules souches pluripotentes induites humaines (hiPSs). En particulier, nous avons ciblé nos travaux sur le rôle de la chaperonne d’histone HIRA dont le gène est localisé dans la région délétée. HIRA est impliquée dans la déposition du variant d’histone H3.3, une histone majeure dans le cerveau. Afin de comprendre l’implication de HIRA dans les manifestations neurologique du syndrome de DiGeorge et en particulier dans la schizophrénie, nous avons développé et optimisé un nouveau protocole pour la différenciation de cellules hiPSCs en progéniteurs neuronaux, neurones corticaux et neurones dopaminergiques. L’ensemble de ces travaux ouvre donc de nouvelles perspectives pour la modélisation d’un grand nombre de pathologies, et dans le contexte du laboratoire, pour l’exploration des mécanismes épigénétiques associés à la variabilité phénotypique dans différentes maladies génétiques. / The DiGeorge syndrome also known as 22q11.2 microdeletion syndrome, is the most common deletion in humans. This deletion is linked to a non-allelic homologous recombination that occurs during meiosis and involves sequences called LCRs for "Low Copy Repeats". Depending on the LCRs involved, different deletions are observed, inducing the loss of approximately 40 genes. The absence of genotype/phenotype correlation in patients and the phenotypical differences regardless of the size of the microdeletion suggests the involvement of additional parameter. The hypothesis of epigenetic changes associated with the onset or variability of symptoms has been suggested but never investigated. In order to tackle this question, we decided to focus our attention of the role of the HIRA histone chaperone encoded by a gene located in the 22q11.2-deleted region. HIRA is involved in the deposition of the H3.3 histone variant, one of the main histone in the brain. In order to determine whether HIRA is implicated in the neurological manifestations in DiGeorge patients and particularly in schizophrenia, we developed and optimized a new protocol for the direct differentiation of human induced pluripotent stem cell (hiPSCs) into neural progenitors, cortical and dopaminergic neurons. In parallel, we developed a new protocol for hiPSCs differentiation toward the skeletal muscle lineage and the production of multinucleated muscle fibers. Altogether, these results open new perspectives for the modeling of a large number of pathologies, and in the context of our laboratory, the exploration of epigenetic mechanisms associated with phenotypic variability in different genetic diseases.

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Stress and anxiety negatively impact the working memory system by competing for executive resources. Broad memory deficits have been reported in individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS). We investigated anxiety and physiological stress reactivity in relation to visuospatial working memory impairments in 20 children with 22q11.2DS and 32 typically developing children (M = 11.10 years, SD = 2.95). Results indicate reduced post-stress RSA recovery and overall increased levels of cortisol in children with 22q11.2DS. Additionally, anxiety mediated the relationship between 22q11.2DS and visuospatial working memory impairment. However, there was no indication that stress response physiology mediated this association. Results suggest that anxiety exacerbates impaired working memory in children with 22q11.2DS. Thus, treatment and intervention methods for children with 22q11.2DS should address anxiety related symptomology.

Intellectual disability (ID) affects approximately 1-3% of the population and is defined as having an IQ below 70 as well as a significant limitation in adaptive behavior. The implementation of chromosomal microarrays (CMA) into the field of clinical genetics has revolutionized the ability to find genetic aberrations responsible for different genetic disorders. Importantly. these technologies have allowed several new microdeletion and microduplication aberrations to be identified that otherwise would have escaped detection using more conventional methods. Finding the genetic etiology of a syndrome and its association to the phenotype is paramount to better health care, provision of tailored therapy, presymptomatic screening, accurate prognosis, recurrence risk evaluation and in some cases prenatal testing. Despite the plethora of new information available, there are still a number of clinical and genetic features we do not fully understand. The aim of this work was to identify regions and syndromes associated with ID by CMA analysis and to make a detailed clinical description of the affected patients’ phenotype. In paper I we studied the 22q11.2 duplication syndrome and presented two familial cases with a description of both their genotype and phenotype. Additionally, 36 cases harboring the duplication were reviewed to further delineate the phenotype of the syndrome. In paper II, we revealed two unrelated patients with a deletion at 6q14.1-q15 and a distinct phenotype. Together with one previously reported patient our study suggests that a novel, clinically recognizable microdeletion syndrome exists in these patients. In paper III the phenotype and genotype of six unrelated patients with partially overlapping microdeletions at 10p12.31-p11.21 were described. Taken together with a previously reported patient we propose that these findings represent a new contiguous gene syndrome. In paper IV, two sisters; one presenting with two tandem interstitial duplications and the other a large deletion over the same region (6q13-q16) were reported. The reason for the CNVs was a maternal de novo translocation. This is the first case describing the genotype and phenotype of this duplicated region at 6q13-q16. In conclusion, four different genetic aberrations involved in the etiology of ID and their corresponding phenotypes and candidate genes have been characterized.