Dissertations / Theses on the topic 'Intellectual disability Genetic aspects'

(Truncated abstract) The aims of this thesis are: (i) To estimate the prevalence of psychiatric illness among persons with intellectual disability and, conversely, the prevalence of intellectual disability among persons with a psychiatric illness; (ii) To describe the disability and service utilisation profile of persons with conjoint disorder; (iii) To examine, in particular, intellectual disability co-occurring with schizophrenia; and (iv) To explore the role of hereditary and environmental (specifically obstetric) risk factors in the aetiology of (i) intellectual disability and (ii) intellectual disability co-occurring with psychiatric illness. This thesis has a special interest in the relationship between intellectual disability and schizophrenia. Where data and sample sizes permit, it explores that relationship at some depth and has included sections on the putative nature of the link between intellectual disability and schizophrenia in the introductory and discussion chapters. To realise its objectives, the thesis comprises a core study focusing on aims (i) – (iii) and a supplementary study whose focus is aim (iv). It also draws on work from an ancillary study completed prior to the period of candidacy...This thesis found that, overall, 31.7% of persons with an intellectual disability had a psychiatric illness; 1.8% of persons with a psychiatric illness had an intellectual disability. The rate of schizophrenia, but not bipolar disorder or unipolar major depression, was greatly increased among cases of conjoint disorder: depending on birth cohort, 3.7-5.2% of individuals with intellectual disability had co-occurring schizophrenia. Down syndrome was much less prevalent among conjoint disorder cases despite being the most predominant cause of intellectual disability while pervasive developmental disorder was over-represented. Persons with conjoint disorder had a more severe clinical profile including higher mortality rates than those with a single disability. The supplementary study confirmed the findings in the core body of work with respect to the extent of conjoint disorder, its severity, and its relationship with pervasive development disorder and Down syndrome. Moreover, the supplementary study and the ancillary influenza study indicated a role for neurodevelopmental insults including obstetric complications in the adverse neuropsychiatric outcomes, with timing of the insult a potentially critical element in defining the specific outcome. The supplementary study also added new information on familiality in intellectual disability. It found that, in addition to parental intellectual disability status and exposure to labour and delivery complications at birth, parental psychiatric status was an independent predictor of intellectual disability in offspring as well as a predictor of conjoint disorder. In conclusion, the facility to collect and integrate records held by separate State administrative health jurisdictions, and to analyse them within the one database has had a marked impact on the capacity for this thesis to estimate the prevalence of conjoint disorder among intellectually disabled and psychiatric populations, and to understand more about its clinical manifestations and aetiological underpinnings.

La déficience intellectuelle (DI) est une trouble du neuro développement caractérisée par une extrême hétérogénéité génétique, avec plus de 700 gènes impliqués dans des formes monogéniques de DI. Cependant un nombre important de gènes restent encore à identifier et les mécanismes physiopathologiques de ces maladies neuro développementales restent encore à comprendre. Mon travail de doctorat a consisté à identifier de nouvelles causes génétiques impliquées dans la DI. En utilisant différentes techniques de séquençage de nouvelle génération, j’ai pu augmenter le taux de diagnostic chez les patients avec DI et identifié plusieurs nouvelles mutations (dans AUTS2, THOC6, etc) et nouveaux gènes (BRPF1, NOVA2, etc) impliqués dans la DI. Pour les moins caractérisés, j'ai effectué des investigations fonctionnelles pour valider leur pathogénicité, caractériser les mécanismes moléculaires qu'ils affectent et identifier leur rôle dans cette maladie. Mes travaux de doctorat permettront d’améliorer et d’accélérer la possibilité d’obtenir un diagnostic moléculaire qui donnera accès à un meilleur suivi et à une meilleure prise en charge pour les patients. Cela permettra également de mieux comprendre les mécanismes physiopathologiques impliqués dans ces troubles neuro développementaux. Ces connaissances aideront éventuellement à identifier de nouvelles cibles thérapeutiques
Intellectual disability (ID) is a group of neurodevelopmental disorders characterized by an extreme genetic heterogeneity, with more than 700 genes currently implicated in Mendelian forms of ID but still some are not yet identified. My PhD project investigates the genetic causes of these monogenic ID by using and combining different NGS techniques. By using this strategy, I reached a relative high diagnostic yield and identified several novel mutations (in AUTS2, THOC6) and genes (BRPF1, NOVA2, etc) involved in ID. For the less characterized ones, I performed functional investigations to prove their pathogenicity, delineate the molecular mechanisms altered and identify their role in this disease. Overall, this work improved and provided new strategies to increase the molecular diagnosis in patients with ID, which is important for their healthcare and better management. Furthermore, the identification and the characterization of novel mutations and genes implicated in ID better delineate the implicated pathophysiological mechanisms, opening the way to potential therapeutic targets

Intellectual disability (ID) is a common neurodevelopmental condition, often caused by genetic defects. De novo variation (DNV) is an important cause of ID, especially in severe or syndromic forms of the disorder. Next generation sequencing has been a successful application for finding pathogenic variation in ID patients. The main focus of this thesis is to use whole exome sequencing (WES) and whole genome sequencing (WGS) to identify pathogenic variants in undiagnosed ID patients. In Paper I, WES was used in family trios to identify pathogenic DNVs in patients diagnosed with ID in combination with epilepsy. This work led to the identification of several DNVs in both new and known disease genes, including the first report of variation in the HECW2 gene in association with neurodevelopmental disorder and epilepsy. Paper II is the first independent validation of PIGG as a disease-causing gene in patients with developmental disorder. We used WES to identify the homozygous variation in PIGG, and transcriptome analysis as well as flow-cytometry studies were used to validate the pathogenicity of the PIGG variation. We discovered that PIGG variation give different effects in different cell types, contributing new insights into the disease mechanism. Paper III is also an application of WES in trio families with patients diagnosed with ID in order to identify causal variants, a strategy similar to that of Paper I. Several pathogenic variants were identified in this study; in particular, the gene NAA15 is highlighted as a new disease gene, and was recently confirmed in independent studies. This study also adds evidence to support that variation in the PUF60 gene is causing the symptoms in patients with Verheij syndrome. In Paper IV, WGS was used to analyze families with consanguineous marriages. All families in this study had been previously analyzed with WES without finding a disease cause. A number of new disease-causing variants were identified in the study, including a first validation of FRMD4A as a disease-associated gene. This study also shows that WGS performs better than WES in finding variants, even for variants in coding parts of the genome.

Intellectual disability (ID) is devastating condition which is defined using three criteria: reduced intellectual ability, deficit in two or more adaptive behaviours, and diagnosis before the age of 18 years. ID can have various causes, but genetic factors are thought to be responsible for up to 50% of cases. ID is a heterogeneous and complex disorder, and more than 800 genes have been implicated in its pathology. Schizophrenia (SZ) is another complex neurodevelopmental condition that also affects the brain and has a partially overlapping genetic basis with ID. This thesis describes work carried out into the genetic basis of ID and SZ. The ID project was focused on ID in consanguineous families recruited in Oman. Next generation sequencing allowed the identification of apparently causative mutations in three out of the six families recruited. The mutations are all novel, although some of them occur in previously associated ID genes. The known ID genes in which novel mutations were identified are TUSC3 (NM_006765: exon2:c.222delA, p.R74 fs) and NHS (NM_198270:exon8: c.C4385G, p.S1462C). A novel LHFPL5 variant (NM_182548:exon2:c.T575C, p.L192P) was also identified in an ID family with hearing loss. In one ID family, mutations in two genes not previously associated with ID were found: ANKRD2 (NM_001129981:exon8:c.C883T, p.R295W) and PDZD8 (PDZD8:NM_173791: exon5:c.2197_2200del, p.733_734del). The SZ project was focused on two SZ families recruited in the UK. Preliminary work on these families had suggested the involvement of homozygosity for genetic variants in the DFNB31 gene and in a region of Chr13q in the pathogenesis of schizophrenia. Further experiments to validate the initial findings included testing the overexpression of the DFNB31 variant (R450C) in the SH-SY5Y cell line, pull-down assay and transcript analysis of the genes located at Chr13q. Identification of the causative mutated gene is an important step in understanding more about the biology of ID and SZ. It also facilitates carrier testing and genetic counselling, and identifies a pathway for potential therapeutic intervention.

This thesis examines collaboratively impoverished frameworks currently existing in services, and then presents a framework within which it is possible to work towards an ethically informed, collaborative engagement between people who have as a common interest, a person with an intellectual disability. The thesis explores three themes that are of great significance to both service providers and other participants in their relation to people with intellectual disability - those of personal identity, advocacy and self-advocacy. The relative impotence of service providers in being able to deal with structural problems concerning these themes, in the absence of a genuinely collaborative endeavor which is driven from an adequately resourced and motivated community base, is demonstrated. Critiques of services offered from philosophical positions are considered. Service models and philosophies adopted as a response to these critiques demonstrate, in their application, the difficulties that services have in operationalizing a pro-active ethical agenda. In considering these philosophies, the power and the role of services in constructing and maintaining devaluing and oppressive meanings associated with the phrase '0person with an intellectual disability' itself, is emphasised. Various ethical discourses are examined and it is shown that these, when undertaken within frameworks of understanding which take the autonomous, rational individual as the subject of the discourse, fail to offer sufficient guidance in the pursuit of the wellbeing of, and respect for, people with intellectual disability. This poses a central issue that any collaborative engagement between stakeholders needs to decide - the status as persons of people with intellectual disability. The issue of ambivalence towards this status, which services seem to perpetuate, poses the central practical question: how is it possible to decisively resolve this ambivalence in favour of the full personhood and humanity of those who are labeled as having intellectual disability? A current service philosophy, Social role Valorisation (SRV), is discussed in considerable detail, to demonstrate the need for this philosophy to be situated in an explicitly ethical framework, in which personhood is acknowledged in all its strangeness, difference and relational diversity, if it is to be utilised collaboratively. The explicit socially normative under-pinning of SRV is shown to reinforce the 'non-person' status of those who fail to meet these normative criteria for acceptance. Thus SRV may on occasions be instrumentally directed to harmful outcomes. The intent of SRV is to protect the life of devalued people, as persons, so there is a need for a more explicitly ethical formulation. The contention of the thesis is that the nature of 'what is valued' with and for people with intellectual disability may only be determined collaboratively, in the context of relationships which give recognition to their intrinsic value as persons, not by reference to some abstract set of social norms. What this intrinsic value is however, can not be according to the attributes selected by some philosophers - autonomy and rationality - as being the essential defining characteristics of persons. Rather, intrinsic value must be a relational concept, derived from those who have a relationship with those with intellectual disability, directed to their respect and wellbeing. for a person with an intellectual disability, to be in relationship with people of such favourable dispositions is of vital importance. Yet it is also important that such people are afforded the recognition, from those less intimately involved, but who exercise power in the situation, that these relationships are the basis for defining social space and place for people who do not fit easily into the system. To be a person with intellectual disability therefore is dependent on the right to be in relationships of interdependency with others, and not be excluded socially as 'defective' because one is not autonomous. The nature of this interdependency, this anti-individualism, as a valid expression of humanity can only be supported through a collaborative engagement.

The number of students with intellectual disabilities who continue studying past compulsory education in Malta is abysmal. This has spurred the choice of my research which aims to identify the factors that affect this phenomenon. This study uses first-hand accounts by individuals with intellectual disabilities on their experience of further education (FE) in Malta and attempts to highlight the associated benefits and barriers experienced. The results of this study have shown that although factors affecting FE inclusion in Malta are varied, the participants of the study focused primarily on the negative barriers arising from past school experience. The level of bullying and isolation experienced in mainstream school environments is considered a predominant factor in the choice of not pursuing FE. Another emerging factor is the lack of choice for students with intellectual disabilities to stand by their own wishes including the choice of whether or not to enter FE. This is considered to be due to an entrenched paternalistic attitude inherent in Maltese society which may originate from the island’s Catholic roots. These socio-cultural attitudes relegate people with intellectual disabilities to passive receivers of charity. It is perhaps these same attitudes that limit the accessibility also within FE in Malta as reported by the study participants. These factors are seen as playing a significant part in the reasons for such low participation of students with intellectual disabilities in FE locally. These barriers limit the opportunities for this student cohort to enjoy the benefits of FE which were identified primarily to be social integration, employment and independence.

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Intellectual disability is characterized by a significant decrease in both cognitive and adaptive functions, affecting 1-3% of the general population. Worldwide is a major socioeconomic problem, with a highly heterogeneous and variable etiology, which may include environmental factors, disorders Mendelian and chromosomal abnormalities, presented alone or in combination. Single gene and chromosomal disorders are considered the cause of intellectual deficiency in 7-37% of cases, while submicroscopic copy number variation occur in 5-15% of cases, especially when associated with multiple congenital abnormalities, and-or dysmorphisms. Genomic microarrays have been extensively used in the studying the genetic causes of intellectual disability, and the chromosomal microarray analysis is recommended as the first-tier cytogenetic diagnostic test for patients with intellectual disability-global developmental delay, autism spectrum disorders and-or multiple congenital anomalies. Genetic counseling is a process that deals with the occurrence or risk of occurrence of a genetic disorder in a family, helping them to understand the contribution of this heritage, involving education and reproductive aspects. The goals include facilitation of informed autonomous choices, education, which includes information on options (available, risks and limitations of those options), as well as provision of emotional support. Promoting, thus, autonomy and adaptation to the diagnosis, with the central tenet the nondirectiveness, requiring the genetic counselor to maintain a neutral stance, supporting and respecting the patient s personal values and decisions. Families of people diagnosed with genetic disorders need to be aware of the importance of going through the process of genetic counseling, and this should be done continuously and according to the need that the facts indicate, with the primary objective the promotion of health and the quality of life.
Deficiência intelectual é caracterizada por uma diminuição significativa em ambas funções cognitivas e adaptativas, afetando de 1 3 % da população em geral. É mundialmente um dos principais problemas sócio-econômicos, com uma etiologia altamente heterogênea e variável, podendo incluir fatores ambientais, desordens mendelianas e anormalidades cromossômicas, apresentados sozinhos ou combinados. Desordens de um único gene e cromossômicas são consideradas a causa de deficiência intelectual em 7-37% dos casos, enquanto que variação número de cópias submicroscópicas ocorrem em 5-15% dos casos, especialmente quando estão associadas com anormalidades congênitas múltiplas e-ou dismorfismos. Microarranjos genômicos têm sido extensivamente usados no estudo das causas genéticas da deficiência intelectual, sendo a análise cromossômica em microarranjos recomendada como teste diagnóstico de primeira escolha para pacientes com deficiência intelectual-atraso no desenvolvimento global, desordem do espectro do autista e-ou anormalidades congênitas múltiplas. Aconselhamento genético é um processo que lida com a ocorrência ou o risco de ocorrência de uma doença genética na família, ajudando-a a compreender a contribuição desta herança, envolvendo aspectos educacionais e reprodutivos. Sua prática visa a facilitação de escolhas autônomas informadas, num processo educacional, incluindo informações sobres as opções (disponibilidade, riscos e limitações destas opções), bem como o fornecimento de um suporte emocional. Promovendo, dessa forma, autonomia e adaptação ao diagnóstico, tendo como dogma central a não diretividade, exigindo do conselheiro geneticista uma posição neutra, apoiando e respeitando valores e decisões pessoais do paciente. Famílias de pessoas diagnosticadas com doenças genéticas precisam ser esclarecidas sobre a importância de passarem pelo processo de aconselhamento genético, e este deve ser feito de forma contínua e de acordo com a necessidade que os fatos indicarem, tendo o objetivo primário a promoção da saúde e a qualidade de vida.

Magister Legum - LLM
Traditional Knowledge (TK) is the long standing wisdom, teachings and practices of indigenous communities which have been passed on orally, in the majority of cases, from generation to generation. TK is expressed in the form, medicine, agriculture, understanding of the ecology, music, dance, stories, folklore, poetry, spiritual, cultural and artistic expressions, and knowledge relating to bio-diversity. This thesis focuses on plant bio-diversity, as part of TK, and the problem of bio-piracy. We attempt a definition of TK; its characteristics; possible measures that can be taken to ensure its protection; and challenges that are likely to be faced in seeking to ensure its protection, first at the global level, then with particular attention to South Africa. Some of the suggested measures include the enactment of sui generis laws to protect plant biodiversity, rather that the adaptation of the existing IP regime. Some of the challenges include unwillingness of some countries to participate in international initiatives, like the US, which is not even a signatory of the CBD, and the difficulty of identifying the persons in whom ownership of the TK should be vested when it is possessed by many communities. This issue is a very sensitive one because there have been numerous cases of bio-piracy in developing countries perpetrated by corporations from industrialised countries. Some of the notable examples of bio-piracy include; The Neem tree from India whose products are used in medicine, toiletries and cosmetics; the Ayahuasca a vine used in India for religious and healing ceremonies; the Asian Turmeric plant used in cooking, cosmetics and medicine, the Hoodia Cactus plant in the Kalahari Desert of southern Africa used by the San people to stave off hunger. These instances have given rise to increased talks about the necessity of a law on the protection of TK relating to bio-diversity in general at the international, regional and national levels. The World Intellectual Property Organisation (WIPO) is working on enacting measures to ensure the protection and conservation of TK at the international level; in 2002 it created nine fact finding commissions on TK in general. These fact finding missions on TK innovation and creativity were undertaken with the intention of seeking possibilities of protecting the intellectual property rights of TK holders. In 2002, The WIPO Intergovernmental Committee on Intellectual Property and Genetic Resources, Traditional Knowledge and Folklore (IGC) was created to continue with this task. The 1993 Convention on Biodiversity (CBD) encourages States to enact measures to implement its provisions on the protection of knowledge, innovations and practices of indigenous and local communities. This trend in protection of TK relating to biological resources has been followed by the Nagoya Protocol of October 2010. The World Trade Organisation (WTO) also makes mention of protecting plant varieties. The research suggests that one could use both Intellectual Property Rights and Sui Generis measures to address and secure protection of TK, and provide compensation to holders for the use of the intellectual property.
South Africa

This thesis provides an analysis of recent attempts to regulate the governance of genetic resources through the initiation of new global commons regimes. These attempts have arisen out of a combination of the growing recognition of genetic resources' value and global nature; a new resurgence in support for the common property paradigm; and, during a period in which the world is becoming increasingly globalised, with many governance competencies moving to the supranational level. They can be viewed as part of a broader effort to proffer the common property approach as a legitimate alternative in the property regime debate: a debate that has increasingly become trapped in the public-private dichotomy at the dawn of the twenty-first century. The aim of this thesis is to investigate the success of these attempts, and offer suggestions about how future attempts might be more successful. While there are a multitude of books, articles, opinion pieces and media reports produced that concern themselves with property theory, intellectual property theory, the efficacy or morality of applying property regimes to living materials, and the threats and promises of globalisation, all of which influence the notion of a potential global genetic commons, relatively little has been written directly on the idea of applying global common property regimes to genetic resource governance issues. The first part of this thesis constructs a theory of a global genetic commons, drawing inspiration from a variety of sources, while the second part tests this theory in order to analyse the outcomes of the recent attempts, and suggest directions for future research. The thesis finds that the conception of a global genetic commons is indeed a valid one, and that while not all attempts so far have been successful, the common property paradigm does offer valuable insights for the future governance of genetic resources at the global level.

Thesis (MEdPsych (Educational Psychology)--Stellenbosch University, 2008.
The research aims to investigate the employment experiences of a South African adult with Down syndrome, and to explore whether this improves the quality of life for this adult across several areas of functioning. This qualitative research design is situated within an interpretive research paradigm. A Case study method was used. Data have been produced using multiple sources and techniques to enhance validity. These include interviews, observation, field notes and questionnaires. Full account has been taken of ethical considerations. The case study shows that this adult with Mosaic Down syndrome and intellectual disability, who is permanently employed in the open labour market, is seen as an asset by the company. Training and support have benefited him and extra supervision and attention needed are minimal. His skills, attitudes, and family support have also enhanced his quality of life. This adult's employment experiences have contributed to a culture of acceptance of and openness to intellectual disability in the formal industrial sector. This is an example of what can be accomplished regardless of intellectual disability. As this is a case study the generalisation of the findings are limited.

Introdução: Com a sofisticação das técnicas de análise do DNA, a medicina moderna tem à sua disposição boas possibilidades para elucidar quadros clínicos indefinidos em pacientes que possuem microrrearranjos cromossômicos complexos. O desenvolvimento da técnica de MLPA (Multiplex ligation-dependent probe amplification) aliado à tecnologia dos arrays (WGAS - whole genome array screening) possibilitou analisar de uma só vez, diferentes regiões de interesse clínico no genoma humano. Objetivo: O presente trabalho teve como objetivo estudar pacientes com atraso de desenvolvimento neuropsicomotor (ADNPM) associado à malformação congênita (MC) com cariótipo prévio normal ou inconclusivo. Material e métodos: Participaram do estudo 71 pacientes com ADNPM associado à MC que foram analisados utilizando o teste de MLPA com os kits P036 e P064, seguido de WGAS com as diferentes plataformas (Agilent, Affymetrix e Illumina). Resultados: Entre os 33 pacientes com alterações patogênicas e de significado clínico incerto (VOUS) encontramos: 12 pacientes com deleção, 5 com duplicação e 16 com duplicações e deleções (dup/del) concomitantes. Foram 29 pacientes com alterações patogênicas conclusivas, 4 pacientes com CNVs classificadas como VOUS e 15 pacientes tiveram resultado de array normal além dos outros 23 que apresentaram alterações benignas, ou por não apresentarem genes na região alterada, ou por serem genes sem fenótipos descritos, ou ainda, as alterações foram herdadas de genitores normais. Na casuística total foram encontrados 4 pacientes com regiões de perda de heterozigosidade. Conclusões: A utilização de uma estratégia combinada utilizando diferentes kits de MLPA, com capacidade para detectar as principais microalterações genômicas patogênicas conhecidas, associada à aplicação do WGAS possibilitou a detecção de alterações submicroscópicas, bem como a correlação clínica adequada para pacientes não diagnosticados pela citogenética clássica. Dessa forma, nosso estudo sugere um novo modelo para a aplicação combinada desses testes que representa uma alternativa de bom custo-benefício para a triagem genômica e definição diagnóstica dos pacientes com quadros sindrômicos complexos e suas famílias
Introduction: The recent technological advances on DNA-based techniques have established in modern medicine good opportunities to elucidate undefined clinical cases in patients with complex chromosomal microrearrangements. The performance of MLPA (Multiplex ligation-dependent probe amplification) technique together with array technologies (WGAS - whole genome array screening) created the possibility of one single experiment to analyze different regions of interest in the human genome. Objective: Patients with psychomotor delay (PSMD) associated with multiple congenital anomalies who had normal or inconclusive G-band-karyotype (MCA) were studied in order to understand the genotype-phenotype correlations. Material and methods: This study involved 71 patients with psychomotor delay (PSMD) associated with multiple congenital anomalies (MCA) analyzed by MLPA (P036 and P064 kits), followed by WGAS different platforms (Agilent, Affymetrix e Illumina®). Results: Among 33 patients with pathogenic and uncertain (VOUS) copy number variations (CNV) were found: 12 deletions, 5 duplications and 16 concomitant duplication and deletion (dup/del). There were 29 patients with conclusive pathogenic findings, 4 patients with VOUS and 16 patients with normal array, but others 23 patients with benign results, which means there is no gene content in the region involved, or because these genes were not linked to phenotype, or even due to CNVs inherited of healthy parents. From the whole casuistic, 4 individuals presented loss of heterozygosity (LOH) regions. Conclusions: The use of a combined strategy of analysis (MLPA - WGAS) with a high capacity to detect pathogenic CNVs allows unraveling microscopic imbalances, and consequently, offers an adequate clinical correlation for patients not previously diagnosed by classical cytogenetics. In conclusion, this study suggests a new model for the combined application of these techniques, which represents an optimal alternative for a genomic screening and diagnostic establishment in patients with rare complex disorders and their families

Les malformations du cortex cérébral (MDC) représentent une cause importante de handicap et d'épilepsie pharmaco-résistante. Le séquençage à haut débit a permis une amélioration considérable de l'identification des bases moléculaires des MDC non syndromiques. Toutefois, certaines formes, notamment les MDC complexes, demeurent inexpliquées. Mon projet de thèse a pour objectif de progresser dans la compréhension des MDC complexes en utilisant deux modèles : les microlissencéphalies (MLIS) et le syndrome d'Aicardi (AIC), une forme syndromique particulière associant des malformations de l'oeil et du cerveau uniquement rapporté chez les filles. L'étude par séquençage d'exome en trios de 16 familles MLIS m'a permis d'identifier et de caractériser un nouveau gène, WDR81, impliqué dans le cycle cellulaire. Par la même stratégie, j'ai pu identifier un variant homozygote pathogène dans TLE1, un partenaire majeur de FOXG1 dans la balance prolifération/différenciation de progéniteurs neuronaux, dans une famille consanguine de microcéphalie postnatale dont le phénotype est proche du syndrome FOXG1. En parallèle, mes travaux ont permis de préciser les spectres phénotypiques associés à RTTN, EPG5, COL4A1, COL4A2, TBR1, KIF5C, KIF2A et FOXG1. La deuxième partie de mon projet avait pour objet l'identification des bases moléculaires du syndrome d'Aicardi à partir d'une cohorte internationale de 19 patientes. Après avoir exclu un biais d'inactivation du chromosome X et la présence de microremaniements chromosomiques, j'ai réalisé un séquençage d'exome en trio. Aucun variant récurrent n'a été retrouvé dans les séquences codantes. Dans un second temps, j'ai testé une approche combinant les données du séquençage de génome et l'analyse du transcriptome (RNA-Seq) sur fibroblastes, me permettant d'identifier des transcrits dérégulés qui étaient impliqués dans le développement du cerveau et de l'oeil. J'ai comparé les résultats de cette analyse avec ceux de l'analyse du génome dans le but d'identifier des variants dans ces gènes candidats. En conclusion, mon travail de thèse a permis d'améliorer la connaissance des bases moléculaires des MDC complexes et d'ouvrir des perspectives de nouveaux mécanismes tels que ceux engageant les gènes WDR81 et EPG5, et le rôle des endosomes et de l'autophagie dans les MDC, et aussi TLE1 comme nouvelle cause de microcéphalies postnatales. Mes travaux ont également permis de générer une collection de données de séquençage haut débit (WES, WGS et RNA-Seq) qui seront mises en commun dans le cadre d'un consortium international afin de développer des nouvelles stratégies d'analyse en particulier pour les séquences non codantes. Cette approche permettra également d'ouvrir la voie vers la compréhension des mécanismes cellulaires impliqués dans la formation du cerveau et de l' œil
Malformations of cortical development (MCD) are a major cause of intellectual disability and drug-resistant epilepsy. Next Generation Sequencing (NGS) has considerably improved the identification of the molecular basis of non-syndromic MCD. However, certain forms, including complex MCD, remain unexplained. My PhD project aimed to improve the understanding of complex MCD using two disorders: Microlissencephaly (MLIS) and Aicardi Syndrome (AIC), the latter associating brain and eye malformations and only reported in girls. Trio Whole Exome Sequencing (WES) performed in 16 MLIS families allowed me to identify and functionally characterize a new MLIS gene, WDR81, in which mutations lead to cell cycle alteration. Moreover, using the same strategy, I was able to identify a pathogenic homozygous variant in TLE1 in a patient from consanguineous family with a postnatal microcephaly, suggestive of a FOXG1-like presentation. Interestingly, TLE1 is a major partner of FOXG1, a gene involved in maintaining the balance between progenitor proliferation and differentiation. In parallel, my work allowed me to redefine the phenotypic spectrum associated with RTTN, EPG5, COL4A1 and COL4A2, TBR1, KIF5C, KIF2A and FOXG1. The second part of my PhD program was aimed at identifying the genetic basis of AIC in an international cohort of 19 patients. After excluding a skewed X chromosome inactivation and the presence of chromosomal rearrangements, I performed WES in trios. The analysis of the data from WES did not allow me to identify any recurrent variants. I therefore tested a new approach combining Whole Genome Sequencing (WGS) and RNA-Sequencing (RNA-Seq) on fibroblast cells. I identified a number of deregulated transcripts implicated in brain and eye development. I compared the results of this analysis with the WGS analysis in order to find variants in these candidate genes. In conclusion, these studies have improved the knowledge of the molecular basis of complex MCD, such as TLE1 in postnatal microcephaly, and revealed the pathogenic mechanisms such as WDR81 in cell cycle progression and EPG5 in endosomes and autophagy. My work has also generated a collection of NGS data (WES, WGS and RNA-Seq) that will be shared in an international consortium to develop new analytical strategies, in particular for the non-coding DNA regions. This novel strategy provides opportunities to improve understanding of the cellular mechanisms involved in brain and eye development

The human neocortex is a highly sophisticated and organized brain structure that is thought to mediate some of the most complex cognitive functions in humans including language and abstract thought. As such, environmental and genetic insults to its normal structure or function can result in devastating neurological conditions including severe epilepsy and intellectual disability. Malformations of cortical development are an increasing collection of disorders that cause neocortical abnormalities due to impaired developmental processes. One recently identified disorder in this class is a thin lissencephaly variant (TLIS) associated with several mutations in the C-terminus death domain of the caspase-2 activation adaptor CRADD (also known as RAIDD). Beyond this, little is known about the mechanism underlying TLIS pathophysiology despite an increasing number of identified individuals suffering from it. In order to better understand this disorder, as well as the normal developmental mechanisms that are impaired in its pathogenesis, I have developed and characterized three murine models by introducing one of a number of different genetic perturbations associated with TLIS. These animal models show behavioral and biochemical abnormalities similar to those seen in human TLIS subjects. Focusing future studies on the developmental processes that underlie differences seen in these mouse models could greatly inform understanding of disease mechanism in humans and assist in the development in therapeutic interventions. My work presented in this dissertation thus effectively establishes a translationally relevant animal model of TLIS.

Tese de Doutoramento em Ciências da Saúde
Neurodevelopmental disorders arise in childhood and are life-long condition that represents many challenges to the patients, their families and society, through public services. Among those, intellectual disability affects 1% of the population in developed countries, encompassing the most common group of neurodevelopmental disorders. Intellectual disability is characterized by cognitive impairment and limitation in functioning capacity and can be cause by exogenous factors (such as maternal alcohol abuse during pregnancy, infections and malnutrition) but it is well established that genetic factors play important roles in its pathophysiology. In ID, as in many others disorders, detecting the underlying genetic cause is a complex and time consuming process yet of great value to the patients and families because it allows the possibility of genetic counseling. In the last years, advances in two major types of technologies allowed great advances in the discovery of new genomic anomalies causing intellectual disability: array comparative genomic hybridization and massive parallel sequencing. Array comparative genomic hybridization allowed a high resolution genome wide investigation of copy number variations leading to the discovery of many novel microdeletion/microduplication syndromes. Massive parallel sequencing evolved in a way that the sequencing of all the genome (or, at a lower cost, all the exons) is now possible to perform in any genetic laboratory in a time and cost-efficient manner, allowing the discovery of many novel variants in previously known and newly discovered intellectual disability genes. These two approaches have provided significantly new insights into the biological pathways associated with intellectual disability and tremendously improved the diagnostic process. In this study we applied these two technologies to the study of the genetic basis of neurodevelopmental disorders. We studied a big group of patients with idiopathic intellectual disability by aCGH (which included two cohorts with different selection criteria - a research and a clinical cohort), a group of patients with a Rett syndrome-like clinical presentation by exome sequencing and re-analyzed exome data from a pediatric heterogeneous cohort. Array comparative genomic hybridization allowed the detection of previously known microdeletion and microduplication syndromes in patients with until then unexplained intellectual disability, with yields of 13% in the research cohort and 18% in the clinical cohort. Importantly it also allowed the discovery of 12 new loci likely to cause neurodevelopmental disease as well as the gathering of additional patients with overlapping genomic imbalances and phenotypic features, allowing the definition of new (rare) syndromes. Massive parallel sequencing – more specifically whole exome sequencing - was applied to a group of patients sharing similar clinical presentation (Rett syndrome-like) and proved to be very effective, leading to the identification of five new genes possibly involved in intellectual disability (HTT, SMARCA1, GABBR2, RHOBTB2 and EIF4G1). It is currently an accepted fact however, that the data generated by exome sequencing at a certain point in time, may not retrieve the genetic cause of the disease. This limitation is often related with the lack of information regarding the genes detected. Given the always increasing knowledge on genes and pathways involved in neurodevelopmental disorders, the need for reevaluation of older and previously unsolved cases emerges. This strategy was also applied in this work and proven to be extremely useful in the clinical context, adding new patients to help establish the relevance of candidate disease genes and raising new candidate genes (DNAJC21, MYOD1 and PAX7). In summary, this work helped to clarify the genetic basis of disease in several patients until then unsolved, as well as to bring forward new candidate loci and genes for intellectual disability and other neurodevelopmental disorders.
This work was supported by Foundation for Science and Technology (FCT) through a PhD studentship (SFRH/BD/90167/2012) and by the Seventh Framework Programme (FP7/2007- 2013) under grant agreement no. 262055. This work was also supported by the FEDER through the Operational Programme Competitiveness Factors - COMPETE and the national funds through the FCT - Foundation for Science and Technology within the projects (POCI-01-0145-FEDER-007038), and by the project NORTE01- 0145-FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).
As perturbações do neurodesenvolvimento surgem na infância e constituem doenças crónicas, criando inúmeras limitações para os doentes, famílias e sociedade – sob a forma de serviços públicos. Entre estas, o défice intelectual (previamente designado atraso mental) afecta 1% da população dos países desenvolvidos, sendo o tipo de doença do neurodesenvolvimento mais comum. O défice intelectual é caracterizado por uma limitação cognitiva e funcional e pode ser causado por factores exógenos (como o consumo materno de álcool durante a gravidez, infeções e malnutrição), sendo no entanto fatores genéticos reconhecidos como muito importantes para a patofisiologia do défice cognitivo. Neste grupo de doenças, assim como em muitas outras, a deteção da causa genética é um processo complexo e demorado mas de grande valor para os doentes e famílias, uma vez que abre portas á possibilidade de aconselhamento genético. Nos últimos anos, avanços em duas grandes tecnologias de diagnóstico genético permitiram a descoberta de novas anomalias genéticas associadas e défice intelectual: array de hibridação genómica comparativa e sequenciação paralela massiva. Os arrays de hibridação genómica comparativa permitiram a análise de alta resolução de todo o genoma na busca de alterações do número de cópias, o que resultou na descoberta de várias novas síndromes associadas microdeleções/microduplicações. A sequenciação paralela massiva desenvolveu-se de uma forma em que a sequenciação de todo o genoma (ou, de forma mais económica, de todos os exões) é agora possível realizar em qualquer laboratório de genética em tempo útil e com um bom custo/benefício, permitindo a descoberta de variantes tanto em genes já conhecidos como em novos genes causadores de défice intelectual. Estas duas abordagens contribuíram significativamente para novas descobertas em vias moleculares associadas com défice intelectual e para o melhoramento do seu diagnóstico. Neste estudo aplicamos estas duas tecnologias ao estudo da base genética de doenças do neurodesenvolvimento. Estudamos por aCGH um grande grupo de doentes com défice intelectual idiopático (o que incluiu dois coortes com diferentes critérios de seleção – um coorte de investigação e um coorte clinico), estudamos por sequenciação de exoma um grupo de doentes com sintomatologia semelhante à síndrome de Rett, e reanalisamos dados de exoma de um grupo heterogéneo de doentes pediátricos. O array de hibridação genómica comparativa permitiu a deteção de microdeleções e microduplicações já conhecidas em doentes até à data com défice intelectual idiopático, com uma taxa de sucesso de 13% no coorte de investigação e de 18% no coorte clinico. Foi também possível a deteção de novos 12 novos loci passíveis de causar doença do neurodesenvolvimento assim como a recolha de doentes adicionais com desequilíbrios genómico e fenótipo sobreponíveis, contribuindo para a definição de novas síndromes raras. A sequenciação paralela massiva – em particular a sequenciação do exoma - foi aplicada a um grupo de doentes com apresentação clinica semelhante (síndrome de Rett-like), revelando-se bem-sucedida na identificação de cinco novos genes possivelmente envolvidos no défice intelectual (HTT, SMARCA1, GABBR2, RHOBTB2 e EIF4G1). Atualmente é facto aceite que os dados gerados por sequenciação do exoma numa determinada altura poderão não levar á descoberta da causa genética da doença. Esta limitação está muitas vezes relacionada com a escassez de informação relativamente aos genes encontrados. Tendo em conta o sempre crescente conhecimento relativo a genes e vias moleculares envolvidas em doenças do neurodesenvolvimento, surge a necessidade de reavaliação de casos antigos não solucionados. Esta estratégia foi também aplicada neste trabalho e provando ser de grande utilidade no contexto clinico, levando à deteção de mais doentes que contribuem para a determinação dos genes candidatos relevantes assim como para a deteção de novos genes candidatos (DNAJC21 , MYOD1 and PAX7 ). Em resumo, este trabalho contribuiu para a clarificação da causa genética de doença em vários doentes até à data não resolvidos, e propõe novos loci candidatos e genes que contribuem para o défice intelectual e outras doenças do neurodesenvolvimento.

Traditional conceptions of autonomy, which highlight the separation of the individual from the social forces around them, contradict a core assumption of sociological thought: that the individual is embedded in society. What then are we to make of autonomy’s cultural power to structure a person’s relationships and commitments? Moreover, how do people maintain autonomous social identities despite the dependencies that structure modern life? I explore these questions through ethnographic inquiry of the daily negotiation of carework and autonomy at an independent living community for adults with intellectual disability. I find that autonomous social identity emerges when autonomous actions are socially and temporally distanced from the actions of others. By framing dependence as a momentary state on the way to a more autonomous future, staff attribute autonomy to participants based on their progress toward future goals. The result is paradoxical. When daily productivity becomes the most salient indicator of autonomy, participants are obligated to be autonomous as a condition for their status as adults. I argue that this obligation to autonomy is a basic mechanism through which social institutions, like adulthood, induce self-governance as a mechanism of social control.

Autism is a neurodevelopmental disorder with an estimated prevalence of 1 in 150 children which makes it more common than childhood cancer and juvenile diabetes. It is estimated that there are more than 100,000 individuals affected by autism in Canada and tens of millions worldwide. It is well established that genetic factors play important role in the pathophysiology of autism; still, our current understanding of these genetic factors is limited and cause of autism remains an important question. During the past decade, after completion of human genome, several new high throughput genome scan technologies have been developed such as microarrays. In the present study, we undertook the challenge of identifying X-chromosomal genes involved in autism by performing genome-wide copy number variation analysis of more than 400 probands with autism using Affymetrix 500K single nucleotide polymorphism (SNP) microarrays. We identified copy number variants implicating several genes on the chromosome X such as PTCHD1, IL1RAPL1, IL1RAPL2 and TSPAN7 as autism candidate genes. We also demonstrated that autism and intellectual disability may share some of these genes as etiologic factors. We performed a comprehensive analysis of PTCHD1 locus and showed that mutations at this locus are associated with autism in ~1 % of the cases. This study also demonstrated that PTCHD1 mutations can cause intellectually disability with or without autism, and that the PTCHD1 protein may act as a receptor in Hedgehog signaling pathway. We have also carried out a detailed analysis of TSPAN7 and IL1RAPL1 to explore the contributions of these genes in autism. We identified one family with intronic deletion of IL1RAPL1 and another case with a missense mutation in this gene, thus implicating this known intellectual disability gene in autism. Our findings highlight the importance of the X chromosome in the etiology of autism, and demonstrate the power of copy number variation analysis coupled with other technologies in identification of disease genes, in particular for complex genetic disorders such as autism.

Lai Ching Ha.
Thesis (Ph.D.)--Chinese University of Hong Kong, 1995.
Includes bibliographical references (leaves 225-243).
Title --- p.1
Abstract --- p.2
Acknowledgments --- p.4
Contents --- p.5
Abbreviations --- p.10
List of Figures --- p.12
List of Tables --- p.15
Chapter Chapter 1 --- Review on Inherited Metabolic Diseases --- p.18
Chapter 1.1 --- Development of the concept of inherited metabolic diseases (IMD) --- p.18
Chapter 1.2 --- Frequency of inherited metabolic diseases --- p.20
Chapter 1.3 --- Molecular basis of mutations in inherited metabolic diseases --- p.22
Chapter 1.3.1 --- Point mutations --- p.22
Chapter 1.3.2 --- Small deletions and insertions --- p.25
Chapter 1.3.3 --- large deletions or duplications --- p.26
Chapter 1.4 --- Pathological consequences of protein defect resultingin IMD --- p.27
Chapter 1.4.1 --- End product --- p.28
Chapter 1.4.2 --- Precursor accumulation --- p.28
Chapter 1.4.3 --- Unusual metabolites --- p.29
Chapter 1.5 --- Heterogeneity of inherited metabolic diseases --- p.29
Chapter 1.5.1 --- Genetic heterogeneity --- p.29
Chapter 1.5.2 --- Variations of expression in different cells --- p.31
Chapter 1.6 --- Diagnosis of inherited metabolic diseases --- p.32
Chapter 1.6.1. --- Biochemical investigations --- p.32
Chapter 1.6.2 --- Identification of accumulated or missing metabolites --- p.33
Chapter 1.6.3 --- Direct analysis of enzymes and proteins --- p.34
Chapter 1.6.4 --- Molecular investigations --- p.34
Chapter 1.7 --- Treatment of inherited metabolic diseases --- p.40
Chapter 1.7.1 --- Treatment at the clinical phenotype level --- p.41
Chapter 1.7.2 --- Treatment at the metabolite level --- p.41
Chapter 1.7.3 --- Treatment at the dysfunctional protein level --- p.43
Chapter 1.7.4 --- Transplantation --- p.44
Chapter 1.7.5 --- Gene therapy --- p.45
Chapter 1.8 --- Inherited metabolic diseases in Hong Kong --- p.47
Chapter 1.9 --- General Aim --- p.48
Chapter Chapter 2 --- Study of Inherited Metabolic Diseases in Mentally Retarded Patients --- p.49
Chapter 2.1 --- Introduction --- p.49
Chapter 2.2 --- Aim --- p.52
Chapter 2.3 --- Materials --- p.53
Chapter 2.3.1 --- Standards --- p.53
Chapter 2.3.2 --- Chemical reagents --- p.53
Chapter 2.3.3 --- Derivatization reagents --- p.54
Chapter 2.3.4 --- Major equipment --- p.54
Chapter 2.4 --- Clinical materials --- p.56
Chapter 2.4.1 --- Subjects --- p.55
Chapter 2.4.2 --- Blood and urine samples --- p.56
Chapter 2.5 --- Methods --- p.57
Chapter 2.5.1 --- General biochemistry tests --- p.57
Chapter 2.5.2 --- Metabolic screening tests --- p.57
Chapter 2.5.3 --- Two-dimensional thin layer chromatography --- p.53
Chapter 2.5.4 --- Identification of urinary organic acids by gas chromatography mass spectroscopy --- p.59
Chapter 2.5.5 --- Amino acid analysis by high performance liquid chromatography --- p.66
Chapter 2.6 --- Results --- p.71
Chapter (A) --- Methodological Aspects
Chapter 2.6.1 --- Identification of urinary organic acids by gas chromatography-mass spectroscopy (GC-MS) --- p.71
Chapter 2.6.2 --- Amino acid analysis by high performance liquid chromatography (HPLC) --- p.86
Chapter (B) --- Patient Investigations
Chapter 2.6.3 --- General biochemistry tests --- p.107
Chapter 2.6.4 --- Serum amino acid profiles --- p.113
Chapter 2.6.5 --- Urinary organic acid analysis --- p.115
Chapter 2.6.6 --- Case reports --- p.119
Chapter 2.7 --- Discussion --- p.123
Chapter 2.7.1 --- Identification of urinary organic acids by gas chromatography-mass spectroscopy (GC-MS) --- p.123
Chapter 2.7.2. --- Amino acid analysis by high performance liquid chromatography (HPLC) --- p.130
Chapter 2.7.3 --- Identification of inherited metabolic diseases (IMD)in an institutionalized mentally retarded patients --- p.136
Chapter Chapter 3 --- Molecular Investigation of Maple Syrup Urine Disease --- p.140
Chapter 3.1 --- Introduction --- p.140
Chapter 3.1.1 --- Branched chain amino acids (BCAA) --- p.140
Chapter 3.1.2 --- Metabolism of branched chain amino acids --- p.142
Chapter 3.1.3 --- Maple syrup urine disease (MSUD) --- p.144
Chapter 3.1.4 --- Classification of maple syrup urine disease --- p.146
Chapter 3.1.5 --- Screening and diagnosis of maple syrup urine disease --- p.148
Chapter 3.1.6 --- Treatment of maple syrup urine disease --- p.150
Chapter 3.1.7. --- Branched chain a-ketoacid dehydrogenase complex (BCKDH) --- p.151
Chapter 3.1.8 --- "Gene features of human E1α,E1β and E2 subunitsin branched chain α-ketoacid dehydrogenase complex" --- p.153
Chapter 3.1.9 --- Molecular defects of the BCKDH gene complex --- p.156
Chapter 3.1.10 --- MSUD in Hong Kong --- p.161
Chapter 3.2 --- Aim --- p.163
Chapter 3.3 --- Materials --- p.164
Chapter 3.3.1 --- Source of skin fibroblasts --- p.164
Chapter 3.3.2 --- Enzymes --- p.164
Chapter 3.3.3 --- DNA markers --- p.164
Chapter 3.3.4 --- Reagent Kits --- p.165
Chapter 3.3.5 --- Primers --- p.165
Chapter 3.3.6 --- Chemical reagents --- p.165
Chapter 3.3.7 --- Nitrocellulose membrane --- p.166
Chapter 3.3.8 --- Antiserum for Western blotting --- p.166
Chapter 3.3.9 --- Radioisotopes --- p.166
Chapter 3.4 --- Methods --- p.168
Chapter 3.4.1 --- Preparation of buffers and solutions --- p.168
Chapter 3.4.2 --- Agarose gel electrophoresis --- p.170
Chapter 3.4.3 --- Preparation of native polyacrylamide gel --- p.171
Chapter 3.4.4 --- Preparation of sodium dodecyl sulfate (SDS) polyacrylamide gel --- p.172
Chapter 3.4.5 --- Preparation of denaturing polyacrylamide gel --- p.173
Chapter 3.4.6 --- Branched chain α-ketoacid dehydrogenase complex enzyme assay --- p.173
Chapter 3.4.7. --- Identification of the affected subunits in BCKDH complex of MSUD patient and her family members --- p.176
Chapter 3.4.8 --- Screening of mutation in the BCKDH subunits by RT-PCR-SSCP --- p.178
Chapter 3.4.9 --- Mutation analysis of whole cDNA fragments of Elα， Elβ and E2 subunits by ds DNA cycle sequencing --- p.184
Chapter 3.5 --- Results --- p.188
Chapter 3.5.1 --- Branched chain α-ketoacid dehydrogenase complex enzyme assay --- p.188
Chapter 3.5.2 --- Identification of the affected subunits in BCKDH complex ofMSUD patient and her family members --- p.188
Chapter 3.5.3 --- Screening of mutation in the BCKDH subunits by RT-PCR-SSCP --- p.192
Chapter 3.5.4 --- "Mutation analysis of whole cDNA fragments of Ela, Elβ and E2 subunits by ds DNA cycle sequencing" --- p.204
Chapter 3.6 --- Discussion --- p.210
Chapter 3.6.1 --- BCKDH activity in the MSUD patient and her family members --- p.210
Chapter 3.6.2 --- Investigation of the mutation sites --- p.212
General Conclusion --- p.222
Appendix --- p.224
References --- p.225

碩士
國立陽明大學
生命科學系暨基因體科學研究所
107
Developmental delay (DD) describes the condition when a child reaches developmental milestones in cognitive, speech/language, fine/gross motor, emotional, social/personal skills and activities of living later than the expected time during infancy and early childhood. Multiple factors may contribute to such delay. Intellectual disability (ID) may also be reflected as DD in early childhood. Clinically, when evaluating a child during early intervention, the pediatrician may consider the probability of genomic aberrations after ruling out socio-psychological or environmental factors. Copy number variations (CNVs) have been regarded as one of the major causes of DD. While array comparative genomic hybridization (aCGH) has been the current golden standard of CNV detection, next generation sequencing (NGS) techniques have evolved into a novel strategy for studying the genetic basis of human diseases, facilitating comprehensive characterization of genomic aberrations, inclusive of both CNVs and single nucleotide variants (SNVs), and analysis of high-resolution sequence data. The aim of this study is to determine the efficiency of whole exome sequencing (WES) as a first-tier diagnostic test in comparison with aCGH for DD. We have enrolled 322 subjects diagnosed with global developmental delay or intellectual disability of unknown cause. All individuals have completed aCGH tests (Positive rate: 17.1%). WES was performed on 34 cases, 24 of whom include both parents, with Agilent SureSelect target enrichment system using Illumina HiSeq2000. Analysis of WES data was conducted using Varseq v2.1.0. In cases whose aCGH tests revealed no positive findings, trio analyses were conducted in hopes of identifying causal variants most closely related to the conditions in the afflicted individuals. We have discovered 4 known rare pathogenic variants that may contribute to GDD/ID out of the 14 trios analyzed so far; they are TUBA1A (p.Arg214His), TMEM240 (p.Val115Met), TUBB2B (p.Ala248Val), and SMARCA2 (p.Pro883Leu). Moreover, 2 of these variants, TUBA1A (p.Arg214His) and SMARCA2 (p.Pro883Leu), correspond with the clinical phenotypes of the affected children, lissencephaly 3 and Nicolaides-Baraitser syndrome, respectively. Furthermore, CNVs in regions that are previously reported to be linked with DD/ID were also discovered in 12 of the cases. We have also included 10 singletons with positive findings in aCGH tests in order to determine the consistency in CNV detection between aCGH and WES tests. Out of the 13 CNVs called using aCGH, we detected CNVs in 11 regions by analyzing WES data. It is also noticed that CNV calling in WES data is more powerful in calling smaller CNV events. Among the 14 trios and 10 probands that have been analyzed so far, 115 CNVs with p-values<0.01 were called per case on average. Spans of these CNVs ranged from 119bp to 15Mbp, with approximately 91 CNVs <100kb, 23 CNVs 100kb-1Mb, and 1 CNVs >1Mb in each case. Duplications account for 65.0% confident CNV calls. Further validation by real-time quantitative PCR (qPCR) was conducted to confirm the precision and accuracy of CNV detection results by WES. CNV calls were divided into 6 strata according to their types and spans. In the 14 trios and 10 singletons, 1% of CNV calls have been drawn from each stratum (30 out of the total 2764 CNVs) for validation, 2 of which were detected in aCGH-negative cases and were previously reported to be associated with DD/ID, and 3 of which lay in the genomic regions that were previously called using aCGH. A total of 12 CNVs (40%) out of the 30 tested CNVs have at least one region that have RQ values that are suggestive or indicative of their CNV types (losses or gains). Here we shall demonstrate the capacity of WES for detecting CNVs and SNVs. WES may be considered a promising first-tier diagnostic tool for its versatility, moderate cost, and the potential to reduce diagnostic odyssey.

Des variants pathogéniques du gène TBC1D24 sont associés à des maladies génétiques dont la majorité sont transmises d’une façon autosomique récessive. Les phénotypes sont variables en termes de présentation clinique et de sévérité. Les formes les plus sévères causent une encéphalopathie épileptique (EIEE16) ou le syndrome DOORS qui est marqué par une surdité, des anomalies des ongles et des doigts, un déficit intellectuel et des convulsions qui sont souvent difficiles à contrôler. D’autres formes d’épilepsie incluent EPRPDC (Rolandic epilepsy with paroxysmal exercise-induce dystonia and writer's cramp), FIME (familial infantile myoclonic epilepsy), et PME (progressive myoclonus epilepsy). Une variant faux-sens spécifique est associée à une surdité autosomique dominante (DFNA65) qui se développe à l’âge adulte. Nous avons écrit un guide de pratique clinique qui inclut une revue de la littérature sur les phénotypes publiés chez les individus avec des variantes pathogénique du gène TBC1D24 avec de recommandations pour le suivi clinique de ces patients. De plus, une cohorte de huit patients avec déficience intellectuelle et épilepsie qui partagent une microdélétion sur le chromosome 16p13.3 contenant le gène TBC1D24 a été assemblée et caractérisée afin de définir un nouveau syndrome génétique. La région critique contient TBC1D24, ATP6V0C et PDPK1. Le phénotype similaire entre les huit individus suggère que l’haploinsuffisance pour TBC1D24, ATP6V0C et PDPK1 cause un nouveau syndrome génétique. L’etude des gènes essentiels pour le phénotype dans cette cohorte aide dans l’identification des nouveaux gènes candidates pour la déficience intellectuelle et épilepsie.
Pathogenic variants in the TBC1D24 gene are associated with genetic disorders, the majority of which are transmitted in an autosomal recessive manner. The phenotypes are variable in terms of clinical presentation and severity. The most severe forms cause epileptic encephalopathy (EIEE16) or DOORS syndrome which is marked by deafness, abnormalities of the nails and fingers, intellectual deficit and convulsions which are often difficult to control. Other forms of epilepsy include EPRPDC (Rolandic epilepsy with paroxysmal exercise-induce dystonia and writer's cramp), FIME (familial infantile myoclonic epilepsy), and PME (progressive myoclonus epilepsy). A specific missense variant is associated with autosomal dominant deafness (DFNA65) which develops in adulthood. A review of the literature of the published phenotypes observed in individuals with pathogenic variants in the TBC1D24 gene is presented here with recommendations for the clinical management of these patients. In addition, a group of eight patients with intellectual disability and epilepsy who share a microdeletion on chromosome 1613.3 containing the TBC1D24 gene were characterized in order to define a new genetic syndrome. The critical region contains TBC1D24, ATP6V0C and PDPK1. The significantly similar phenotype shared by the eight individuals suggests that haploinsufficiency for TBC1D24, ATP6V0C and PDPK1 causes a new genetic syndrome. Knowledge of the genes essential for the phenotype in this cohort helps in the identification of new candidate genes for intellectual disability and epilepsy.

Adolescence is considered a time of change and, to some extent, upheaval. Psychological Sense of Community has been utilised as a framework for understanding adolescents’ experiences in their communities. The present study explored the experiences of 10 adolescents from two urban schools in eastern Australia, a specialist school for students with a mild intellectual disability, and a mainstream school. Using Photovoice, an ethnographic research method utilising photographs generated by the research participants as the primary data source, the participants were actively engaged in taking photographs about their day to day lives in their communities. The photographs were supplemented by individual semi-structured interviews and small group discussions. Results confirmed the importance of meaningful relationships with family, neighbours, pets and peers for participants from both groups. Levels of participation in a range of activities were also explored. Concepts of community including place, neighbourhood, virtual communities and communities of interest were elicited from participants. Many aspects of adolescent life were similar for both groups, although family provided more support to participants with an intellectual disability in enabling them to participate actively within the community. Discussions about spirituality were more prominent with participants without a disability, possibly reflecting language and cognitive abilities. All participants expressed concerns about growing up, letting go of childhood and facing responsibilities associated with adulthood. Overall, the present study suggested that the day to day experiences of adolescents from both groups were similar with social interactions underpinning what they considered to be important.