Clefts of the lip and/or palate (CL/P) are one of the most common birth defects in the world occurring about every 1 in 700 live births. Individuals with non-syndromic clefting (NSCL/P) account for about 70% of all cleft cases and exhibit a cleft only whereas syndromic occurrences (SCL/P) include additional cognitive or structural abnormalities. Linkage, genome-wide association, candidate gene, animal model, sequencing and copy number variant (CNV) analyses have been used to study CL/P and have established that it is a heterogeneous, complex disorder. However, the impact of identified sequence variants on protein structure and the contribution of structural genetic variation to CL/P remains poorly understood. In our first analysis we reassessed the phenotype of a 30-year-old individual of SCL/P and noticed phenotypic overlap with Hartsfield syndrome, a rare syndrome resulting from sequence variants in Fibroblast growth factor 1 (FGFR1). We sequenced the coding region of FGFR1 and identified a novel, de novo variant. Due to the fact sequence variants in FGFR1 contribute to multiple syndromes encompassing a wide phenotypic spectrum, we performed an extensive literature search to record every published sequence variant of FGFR1 and mapped it to the protein structure by disease and phenotype. Although no statistically significant protein domain-phenotype correlations were identified, many regions neared significance. This work stresses the need for systematic, comprehensive phenotyping of patients and provides a method for assessing the impact of the location of sequence variants within the 3D structure of the protein. Although rare and common CNVs have been identified in individuals with CL/P, prior to our work no large-scale studies of rare CNVs for the identification of novel clefting genes had been performed. For our second set of analyses, we conducted two such studies, first focusing on a smaller cohort of 140 individuals with NSCL/P from the Philippines to establish our informatic and functional validation pipeline. We used whole-genome tiling arrays to assess rare deletions overlapping genes not previously implicated in clefting, and identified one deletion overlapping Isthmin1 (ISM1) and a deletion just 3’ of the gene in a second affected individual. Functional validation of Ism1 in Xenopus laevis showed strong expression in structures necessary for craniofacial development, and morpholino and CRISPR/Cas9 knockdown of Ism1 resulted in a median cleft lip in some embryos, establishing ISM1 as a novel craniofacial patterning gene. We then expanded our study and assessed genomic CNVs in 1021 individuals with NSCL/P and 81 individuals with SCL/P, finding no differences in CNV number, load or burden between these groups. We also identified 8 putative clefting genes overlapped by deletions in two or more individuals but at a rare (< 1% frequency) in the cohort. Functional validation of these genes using CRISPR/Cas9 in zebrafish and Xenopus tropicalis is currently underway. This work has identified a novel sequence variant leading to the diagnosis of Hartsfield syndrome in an individual with SCL/P, developed an innovative method for assessing the impact of sequence variation on protein structure, improved our understanding of the contribution of CNVs to SCL/P and NSCL/P and identified several putative novel clefting loci which may help explain a portion of the missing heritability of CL/P.

The 16p11.2 copy-number variant (CNV) represents a well-characterized, high-risk factor for autism spectrum disorder that additionally predisposes deletion carriers (16pdel) to increased head circumference, known as macrocephaly. The 16p11.2 CNV consists of 29 known genes, many of which are associated with neurobiological processes relevant for macrocephaly such as cell proliferation and apoptosis, differentiation and cell growth. Our lab’s previous work has demonstrated that induced pluripotent stem cell (iPSC)-derived neurons from 16pdel carriers show altered cellular morphology related to growth, which include increased soma size, total dendritic length and dendritic complexity. However, specific CNV genes responsible for these phenotypes have not been established. Here, we investigate the relationship between three 16p11.2 genes and the observed cellular phenotypes. We differentiated neurons from control iPSC-derived neural progenitor cells (NPCs) and used short hairpin RNA (shRNA) to reduce the expression of these CNV genes: KCTD13, MAPK3 and C16ORF53. We then assessed neuronal morphology by evaluating soma size, total dendritic length and dendritic complexity. We demonstrate that knocking down KCTD13 and C16ORF53 increases soma size and total dendrite length, respectively, similar to that observed in 16pdel iPSC-derived neurons. For this reason, we speculate that these genes may have a role in cell growth and might underlie macrocephaly. Thus, our study investigates genes in the 16p11.2 CNV that contribute to neuronal morphology, which may have a role in influencing brain size.

No description available.

L’hypertension artérielle essentielle (HTA) est une pathologie complexe, multifactorielle et à forte composante génétique. L’impact de la variabilité dans le nombre de copies sur l’HTA est encore peu connu. Nous envisagions que des variants dans le nombre de copies (CNVs) communs pourraient augmenter ou diminuer le risque pour l’HTA. Nous avons exploré cette hypothèse en réalisant des associations pangénomiques de CNVs avec l’HTA et avec l’HTA et le diabète de type 2 (DT2), chez 21 familles du Saguenay-Lac-St-Jean (SLSJ) caractérisées par un développement précoce de l’HTA et de la dyslipidémie. Pour la réplication, nous disposions, d’une part, de 3349 sujets diabétiques de la cohorte ADVANCE sélectionnés pour des complications vasculaires. D’autre part, de 187 sujets de la cohorte Tchèque Post-MONICA (CTPM), choisis selon la présence/absence d’albuminurie et/ou de syndrome métabolique. Finalement, 134 sujets de la cohorte CARTaGENE ont été analysés pour la validation fonctionnelle. Nous avons détecté deux nouveaux loci, régions de CNVs (CNVRs) à effets quantitatifs sur 17q21.31, associés à l’hypertension et au DT2 chez les sujets SLSJ et associés à l’hypertension chez les diabétiques ADVANCE. Un modèle statistique incluant les deux variants a permis de souligner le rôle essentiel du locus CNVR1 sur l’insulino-résistance, la précocité et la durée du diabète, ainsi que sur le risque cardiovasculaire. CNVR1 régule l’expression du pseudogène LOC644172 dont le dosage est associé à la prévalence de l’HTA, du DT2 et plus particulièrement au risque cardiovasculaire et à l’âge vasculaire (P<2×10-16). Nos résultats suggèrent que les porteurs de la duplication au locus CNVR1 développent précocement une anomalie de la fonction bêta pancréatique et de l’insulino-résistance, dues à un dosage élevé de LOC644172 qui perturberait, en retour, la régulation du gène paralogue fonctionnel, MAPK8IP1. Nous avons également avons identifié six CNVRs hautement hérités et associés à l'HTA chez les sujets SLSJ. Le score des effets combinés de ces CNVRs est apparu positivement et étroitement relié à la prévalence de l’HTA (P=2×10-10) et à l’âge de diagnostic de l’HTA. Dans la population SLSJ, le score des effets combinés présente une statistique C, pour l’HTA, de 0.71 et apparaît aussi performant que le score de risque Framingham pour la prédiction de l’HTA chez les moins de 25 ans. Un seul nouveau locus de CNVR sur 19q13.12, où la délétion est associée à un risque pour l’HTA, a été confirmé chez les Caucasiens CTPM. Ce CNVR englobe le gène FFAR3. Chez la souris, il a été démontré que l’action hypotensive du propionate est en partie médiée par Ffar3, à travers une interférence entre la flore intestinale et les systèmes cardiovasculaire et rénal. Les CNVRs identifiées dans cette étude, affectent des gènes ou sont localisées dans des QTLs reliés majoritairement aux réponses inflammatoires et immunitaires, au système rénal ainsi qu’aux lésions/réparations rénales ou à la spéciation. Cette étude suggère que l’étiologie de l’HTA ou de l’HTA associée au DT2 est affectée par des effets additifs ou interactifs de CNVRs. / Essential hypertension (HT) is a multifactorial complex disease with a strong genetic component. However, little is known about the effects of copy number variance on HT. We hypothesized common Copy Number Variants (CNVs) could increase or decrease the risk for HT. We performed GWAS of CNVs with HT and, with HT and Type 2 Diabetes (T2D), in 21 families of the Saguenay-Lac-St-Jean region of Quebec (FC) affected by early-onset hypertension and dyslipidemia. Replication was tested in a cohort of 3349 unrelated diabetic subjects of Caucasian origin from the ADVANCE trial. Replication was also tested in 187 individuals from the Czech Post-Monica (CPM) cross-sectional survey, ascertained by the presence/absence of albuminuria and/or metabolic syndrome. We performed locus-specific transcriptional analyses in 134 subjects from the CARTaGENE population cohort. We identified two CNV Regions (CNVRs), at 17q21.31, associated with HT and T2D in FC and associated with hypertension in ADVANCE diabetics. A statistical model of association including both CNVRs underlined the main effect size of CNVR1 on insulin resistance, T2D early onset and duration, and risk for cardiovascular diseases (CVD). CNVR1 appeared to influence LOC644172 expression, whose transcript abundance was associated with the prevalence of HT and T2D, and strongly with the risk of CVD and vascular age (P<2×10-16). Our results suggest carriers of copy-number gain at these 17q21.31 loci, principally at the CNVR1 locus, undergo premature β-cell functional deregulation and insulin resistance, due to increase dosage of the LOC644172 pseudogene, which might in turn affect the regulation of expression of its functional paralog, MAPK8IP1. We also report six different CNVR loci, highly heritable and contributing to the risk of hypertension, in French Canadians. The combined CNV risk score appeared robustly related to prevalence of hypertension (p=2×10-10) and age at diagnosis of hypertension. In FC, this combined CNV risk score model showed a C-statistic of 0.71 for HT and appeared as powerful as Framingham HT risk score in predicting hypertension in individuals aged less than 25. We validated the association of a new locus, 19q13.12 deletion-CNVR, with hypertension, in CPM. FFAR3 surrounds this 19q13.12 deletion-CNVR. It has been demonstrated that in mice, a portion of propionate hypotensive effect is mediated by Ffar3, and involves a cross-talk between the gut microbiota and the renal-cardiovascular system. The identified CNVRs appear to influence genes and QTLs mainly related to immune and inflammatory responses and renal damaged and repair. Some CNVRs are exclusive to primates. This study suggests that additive and interactive actions of multiple copy-number variants are involved in the etiology of hypertension or of hypertension associated with T2D.

Schizophrenia is a complex disorder affecting 1% of the population and is highly heritable, but the majority of contributing genetic factors has remained elusive. Current risk estimates for clinical practice are primarily determined by family history and associated empirical risk. Copy number variants (CNVs) may hold the key to explaining the missing heritability in schizophrenia research; schizophrenia risk estimates as high as 30% have been found for the most-studied CNV associated with schizophrenia, 22q11. Currently, there are methods to identify CNVs though previously collected data from SNP microarrays that would facilitate these types of studies. To determine if algorithms that call CNVs from microarray data are robust four genomic regions with putative CNVs called by the Wellcome Trust Consortium using Birdseye in Birdsuite with Affymetrix 6.0 array raw SNP intensities, primarily affecting genes CHD1L, COX5B, PAK7, ZFYVE20, were validated using Taqman real-time qPCR assays in 29 samples by research groups at VCU and Dublin. CNVs called from the algorithm were 100% validated at VCU though there were false negatives from the algorithm that were validated. Two samples at loci with putative duplications were not called by the Dublin group, which may be because of differing sensitivities of the Taqman assays to be able to detect a 50% difference in copy number between duplications and diploid controls, or because of another technical or analytical difference between the two sites. Deletion frequency of one common CNV found in the gene ERBB4, was assessed by qPCR in both Irish singleton (ICCSS) and Irish family (IHDSF) samples and compared with Irish control (Trinity Biobank) and North American control populations. The ERBB4 deletion frequency was not significantly different when comparing the Irish controls to the Irish singleton or the Irish family samples though the family samples were different when compared against the North American control population, which suggests population stratification, rather than a true association between ERBB4 and increased schizophrenia risk. Current clinical practice has been improved by knowledge and evaluation of CNV-related disorders that include risk for psychosis and additional phenotypes. Genotyping of individuals with known psychosis has led to improved patient care for non-psychosis-related phenotypes associated with CNVs. Individuals with suspected genomic disorders that are found to have CNVs can be counseled on potential psychosis risk and potential risk to their offspring. Recurrent CNVs may hold promise in future clinical practice in order to individualize risk estimates in the general patient population, and increase the number of individuals able to receive anticipatory treatment to minimize disease severity.

O Transtorno de Déficit de Atenção e Hiperatividade (TDAH) é a doença do neurodesenvolvimento mais comum na infância, afetando cerca de 5,8% de crianças e adolescentes no mundo. Muitos estudos vêm tentando investigar a suscetibilidade genética em TDAH, mas sem muito sucesso. Este estudo teve como objetivo analisar variantes raras e comuns contribuindo para a arquitetura genética do TDAH. Foram gerados os primeiros dados de exoma de TDAH de 30 trios brasileiros em que o filho foi diagnosticado com TDAH esporádico. Foram analisados tanto variações de único nucleotídeo (ou SNVs, single-nucleotide variants) quanto variações de número de cópias (ou CNVs, copy-number variants), tanto nesses trios quanto em outros conjuntos de dados, incluindo uma amostra brasileira de 503 crianças/adolescentes controles, bem como resultados previamente publicados em quatro estudos com variação de número de cópias e uma meta-análise de estudos de associação ao longo do genoma. Tanto os trios quanto os controles fazem parte da Coorte de Escolares de Alto Risco para o desenvolvimento de Psicopatologia e Resiliência na Infância do Instituto Nacional de Psiquiatria do Desenvolvimento (INPD). Os resultados de trios brasileiros mostraram três padrões marcantes: casos com variações herdadas e somente SNVs de novo ou CNVs de novo, e casos somente com variações herdadas. Embora o tamanho amostral seja pequeno, pudemos ver que diferentes comorbidades são mais frequentes em casos somente com variações herdadas. Após explorarmos a composição de variações nos probandos brasileiros, foram selecionados genes recorrentes entre amostras do nosso estudo ou em bancos de dados públicos. Além disso, usando somente genes expressos no cérebro (amostras pós-mortem dos projetos Brain Atlas e Genotype-Tissue Expression), construímos uma rede de interação proteína-proteína \"in silico\" com interações físicas confirmadas por pelo menos duas fontes. Análises topológicas e funcionais dos genes da rede mostraram genes relacionados a sinapse, adesão celular, vias glutamatérgicas e serotonérgicas, o que confirma achados de trabalhos independentes na literatura indicando ainda novos genes e variantes genéticas nessas vias. / Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neuro-developmental disorder in children, affecting 5.8% of children and adolescents in the world. Many studies have attempted to investigate the genetic susceptibility of ADHD without much success. The present study aimed to analyze rare and common variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios where the children were diagnosed with sporadic ADHD. We analyzed both single-nucleotide variants (SNVs) and copy-number variants (CNVs) in these trios and across multiple datasets, including a Brazilian sample of 503 children/adolescent controls from the High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of four CNV studies of ADHD involving children/adolescent Caucasian samples. The results from the Brazilian trios showed 3 major patterns: cases with inherited variations and de novo SNVs or de novo CNVs and cases with only inherited variations. Although the sample size is small, we could see that various comorbidities are more frequent in cases with only inherited variants. After exploring the rare variant composition in our 30 cases we selected genes with variations (SNVs or located in CNV regions) in our trio analysis that are recurrent in the families analyzed or in public data sets. Moreover, using only genes expressed in brain (post-mortem samples from Brain Atlas and The Genotype-Tissue Expression project), we constructed an in silico protein-protein interaction (PPI) network, with physical interactions confirmed by at least two sources. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

L’hypertension artérielle essentielle (HTA) est une pathologie complexe, multifactorielle et à forte composante génétique. L’impact de la variabilité dans le nombre de copies sur l’HTA est encore peu connu. Nous envisagions que des variants dans le nombre de copies (CNVs) communs pourraient augmenter ou diminuer le risque pour l’HTA. Nous avons exploré cette hypothèse en réalisant des associations pangénomiques de CNVs avec l’HTA et avec l’HTA et le diabète de type 2 (DT2), chez 21 familles du Saguenay-Lac-St-Jean (SLSJ) caractérisées par un développement précoce de l’HTA et de la dyslipidémie. Pour la réplication, nous disposions, d’une part, de 3349 sujets diabétiques de la cohorte ADVANCE sélectionnés pour des complications vasculaires. D’autre part, de 187 sujets de la cohorte Tchèque Post-MONICA (CTPM), choisis selon la présence/absence d’albuminurie et/ou de syndrome métabolique. Finalement, 134 sujets de la cohorte CARTaGENE ont été analysés pour la validation fonctionnelle. Nous avons détecté deux nouveaux loci, régions de CNVs (CNVRs) à effets quantitatifs sur 17q21.31, associés à l’hypertension et au DT2 chez les sujets SLSJ et associés à l’hypertension chez les diabétiques ADVANCE. Un modèle statistique incluant les deux variants a permis de souligner le rôle essentiel du locus CNVR1 sur l’insulino-résistance, la précocité et la durée du diabète, ainsi que sur le risque cardiovasculaire. CNVR1 régule l’expression du pseudogène LOC644172 dont le dosage est associé à la prévalence de l’HTA, du DT2 et plus particulièrement au risque cardiovasculaire et à l’âge vasculaire (P<2×10-16). Nos résultats suggèrent que les porteurs de la duplication au locus CNVR1 développent précocement une anomalie de la fonction bêta pancréatique et de l’insulino-résistance, dues à un dosage élevé de LOC644172 qui perturberait, en retour, la régulation du gène paralogue fonctionnel, MAPK8IP1. Nous avons également avons identifié six CNVRs hautement hérités et associés à l'HTA chez les sujets SLSJ. Le score des effets combinés de ces CNVRs est apparu positivement et étroitement relié à la prévalence de l’HTA (P=2×10-10) et à l’âge de diagnostic de l’HTA. Dans la population SLSJ, le score des effets combinés présente une statistique C, pour l’HTA, de 0.71 et apparaît aussi performant que le score de risque Framingham pour la prédiction de l’HTA chez les moins de 25 ans. Un seul nouveau locus de CNVR sur 19q13.12, où la délétion est associée à un risque pour l’HTA, a été confirmé chez les Caucasiens CTPM. Ce CNVR englobe le gène FFAR3. Chez la souris, il a été démontré que l’action hypotensive du propionate est en partie médiée par Ffar3, à travers une interférence entre la flore intestinale et les systèmes cardiovasculaire et rénal. Les CNVRs identifiées dans cette étude, affectent des gènes ou sont localisées dans des QTLs reliés majoritairement aux réponses inflammatoires et immunitaires, au système rénal ainsi qu’aux lésions/réparations rénales ou à la spéciation. Cette étude suggère que l’étiologie de l’HTA ou de l’HTA associée au DT2 est affectée par des effets additifs ou interactifs de CNVRs. / Essential hypertension (HT) is a multifactorial complex disease with a strong genetic component. However, little is known about the effects of copy number variance on HT. We hypothesized common Copy Number Variants (CNVs) could increase or decrease the risk for HT. We performed GWAS of CNVs with HT and, with HT and Type 2 Diabetes (T2D), in 21 families of the Saguenay-Lac-St-Jean region of Quebec (FC) affected by early-onset hypertension and dyslipidemia. Replication was tested in a cohort of 3349 unrelated diabetic subjects of Caucasian origin from the ADVANCE trial. Replication was also tested in 187 individuals from the Czech Post-Monica (CPM) cross-sectional survey, ascertained by the presence/absence of albuminuria and/or metabolic syndrome. We performed locus-specific transcriptional analyses in 134 subjects from the CARTaGENE population cohort. We identified two CNV Regions (CNVRs), at 17q21.31, associated with HT and T2D in FC and associated with hypertension in ADVANCE diabetics. A statistical model of association including both CNVRs underlined the main effect size of CNVR1 on insulin resistance, T2D early onset and duration, and risk for cardiovascular diseases (CVD). CNVR1 appeared to influence LOC644172 expression, whose transcript abundance was associated with the prevalence of HT and T2D, and strongly with the risk of CVD and vascular age (P<2×10-16). Our results suggest carriers of copy-number gain at these 17q21.31 loci, principally at the CNVR1 locus, undergo premature β-cell functional deregulation and insulin resistance, due to increase dosage of the LOC644172 pseudogene, which might in turn affect the regulation of expression of its functional paralog, MAPK8IP1. We also report six different CNVR loci, highly heritable and contributing to the risk of hypertension, in French Canadians. The combined CNV risk score appeared robustly related to prevalence of hypertension (p=2×10-10) and age at diagnosis of hypertension. In FC, this combined CNV risk score model showed a C-statistic of 0.71 for HT and appeared as powerful as Framingham HT risk score in predicting hypertension in individuals aged less than 25. We validated the association of a new locus, 19q13.12 deletion-CNVR, with hypertension, in CPM. FFAR3 surrounds this 19q13.12 deletion-CNVR. It has been demonstrated that in mice, a portion of propionate hypotensive effect is mediated by Ffar3, and involves a cross-talk between the gut microbiota and the renal-cardiovascular system. The identified CNVRs appear to influence genes and QTLs mainly related to immune and inflammatory responses and renal damaged and repair. Some CNVRs are exclusive to primates. This study suggests that additive and interactive actions of multiple copy-number variants are involved in the etiology of hypertension or of hypertension associated with T2D.

O Transtorno de Déficit de Atenção e Hiperatividade (TDAH) é a doença do neurodesenvolvimento mais comum na infância, afetando cerca de 5,8% de crianças e adolescentes no mundo. Muitos estudos vêm tentando investigar a suscetibilidade genética em TDAH, mas sem muito sucesso. Este estudo teve como objetivo analisar variantes raras e comuns contribuindo para a arquitetura genética do TDAH. Foram gerados os primeiros dados de exoma de TDAH de 30 trios brasileiros em que o filho foi diagnosticado com TDAH esporádico. Foram analisados tanto variações de único nucleotídeo (ou SNVs, single-nucleotide variants) quanto variações de número de cópias (ou CNVs, copy-number variants), tanto nesses trios quanto em outros conjuntos de dados, incluindo uma amostra brasileira de 503 crianças/adolescentes controles, bem como resultados previamente publicados em quatro estudos com variação de número de cópias e uma meta-análise de estudos de associação ao longo do genoma. Tanto os trios quanto os controles fazem parte da Coorte de Escolares de Alto Risco para o desenvolvimento de Psicopatologia e Resiliência na Infância do Instituto Nacional de Psiquiatria do Desenvolvimento (INPD). Os resultados de trios brasileiros mostraram três padrões marcantes: casos com variações herdadas e somente SNVs de novo ou CNVs de novo, e casos somente com variações herdadas. Embora o tamanho amostral seja pequeno, pudemos ver que diferentes comorbidades são mais frequentes em casos somente com variações herdadas. Após explorarmos a composição de variações nos probandos brasileiros, foram selecionados genes recorrentes entre amostras do nosso estudo ou em bancos de dados públicos. Além disso, usando somente genes expressos no cérebro (amostras pós-mortem dos projetos Brain Atlas e Genotype-Tissue Expression), construímos uma rede de interação proteína-proteína \"in silico\" com interações físicas confirmadas por pelo menos duas fontes. Análises topológicas e funcionais dos genes da rede mostraram genes relacionados a sinapse, adesão celular, vias glutamatérgicas e serotonérgicas, o que confirma achados de trabalhos independentes na literatura indicando ainda novos genes e variantes genéticas nessas vias. / Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neuro-developmental disorder in children, affecting 5.8% of children and adolescents in the world. Many studies have attempted to investigate the genetic susceptibility of ADHD without much success. The present study aimed to analyze rare and common variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios where the children were diagnosed with sporadic ADHD. We analyzed both single-nucleotide variants (SNVs) and copy-number variants (CNVs) in these trios and across multiple datasets, including a Brazilian sample of 503 children/adolescent controls from the High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of four CNV studies of ADHD involving children/adolescent Caucasian samples. The results from the Brazilian trios showed 3 major patterns: cases with inherited variations and de novo SNVs or de novo CNVs and cases with only inherited variations. Although the sample size is small, we could see that various comorbidities are more frequent in cases with only inherited variants. After exploring the rare variant composition in our 30 cases we selected genes with variations (SNVs or located in CNV regions) in our trio analysis that are recurrent in the families analyzed or in public data sets. Moreover, using only genes expressed in brain (post-mortem samples from Brain Atlas and The Genotype-Tissue Expression project), we constructed an in silico protein-protein interaction (PPI) network, with physical interactions confirmed by at least two sources. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

Carriers of apparently balanced chromosomal aberrations (BCA) are usually phenotypically normal. However, it has been estimated that up to 27% of these BCA may be associated with an abnormal phenotype, most often caused by cryptic imbalances at the breakpoints, gene disruption by the breakpoint or via the position effect. In contrast to conventional karyotyping, molecular cytogenetic techniques enable more detailed BCA characterization and better correlation between genotype and phenotype of the patient. The aim of this thesis was to evaluate the presence of copy number variants (CNVs) at breakpoints or elsewhere in the genome in patients with abnormal phenotype who carry de novo or inherited BCA. 54 BCA were investigated using array CGH (20 de novo cases, 27 inherited and 7 cases of unknown origin) including 32 reciprocal translocations, 6 robertsonian translocations, 12 inversions and 4 complex chromosomal rearrangements. If possible, the parents were also examined to ascertain the inheritance of the relevant CNVs. In order to specify microarray findings or exclude gene disruption, FISH was used in selected patients. Among the patients included, in 31,5% (17/54) at least one (in 8 patients more than one) significant CNV was detected. Four cases carried cryptic imbalances only at the breakpoints,...

No description available.