Impacto das variações de número de cópias (CNVs) da região 22q11.2 na população geral e atuação de CNVs modificadoras na síndrome da deleção 22q11.2
Data
2023-01-24
Autores
Souza, Malú Zamariolli de 
Orientadores
Melaragno, Maria Isabel de Souza Aranha
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A região 22q11.2 é altamente complexa e predisposta à ocorrência de rearranjos genômicos como deleções e duplicações. Essas variantes genéticas, as chamadas variações de número de cópias (CNVs), têm o potencial de acarretar traços leves e moderados na população geral como também culminar em fenótipos mais graves, característicos de síndromes clínicas.
Na presente tese, múltiplas abordagens foram aplicadas na tentativa de ampliar a compreensão acerca de diversos aspectos relacionados à região 22q11.2. No primeiro estudo, objetivou-se identificar CNVs modificadoras, fora da região 22q11.2, para os defeitos cardíacos congênitos (DCC) em uma coorte de 117 pacientes com a síndrome da deleção 22q11.2 (SD22q11.2). Após a detecção de CNVs a partir da metodologia de SNP- array e controle de qualidade, foram identificadas 50 CNVs em 38 pacientes. O conteúdo gênico dessas CNVs e as vias biológias relacionadas foram examinados sendo esses comparados entre os pacientes com e sem DCC. Verificamos que genes afetados por CNVs em pacientes com DCC estavam enriquecidos para vários termos funcionais relacionados à ubiquitinação, sítios de ligação de fator de transcrição e alvos de miRNA, destacando a complexidade do fenótipo. Genes relacionados ao desenvolvimento e à patogênese cardíaca foram identificados em ambos os grupos de pacientes. Esses genes e vias enriquecidas podem indicar novos modificadores do fenótipo cardíaco em pacientes com SD22q11.2.
No segundo estudo aqui apresentado, o impacto de CNVs na região 22q11.2 em diferentes fenótipos foi avaliado na coorte populacional do UK Biobank (N = 405.324 indivíduos). Para isso, termos do banco Human Phenotype Ontology (HPO) associados a algum dos 90 genes abrangidos pela região 22q11.2 foram mapeados, chegando-se a 170 fenótipos disponíveis no UK Biobank. Em seguida, foi avaliada a associação entre esses traços fenotípicos e o estado de número de cópias das sondas de SNP-array presentes na região 22q11.2. Foram encontradas associações significantes para 17 fenótipos em diferentes modelos, mostrando que duplicações e deleções agem sobre essas características por meio de mecanismos distintos. O efeito causal do nível de expressão dos genes presentes em 22q11.2 nas características associadas foi avaliado por meio da metodologia de transcriptome-wide mendelian randomization (TWMR), que revelou efeito do gene ARVCF no índice de massa corpórea e do gene DGCR6 no volume médio de plaquetas. Além disso, a abordagem de multivariable mendelian randomization (MVMR) sugeriu um papel predominante da pleiotropia horizontal para as CNVs da região.
Juntos esses trabalhos fornecem novas evidências para aumentar a compreensão acerca da complexa região 22q11.2 e dos mecanismos envolvidos na variabilidade clínica da SD22q11.2.
The 22q11.2 region is highly complex and predisposed to the occurrence of genomic rearrangements such as deletions and duplications. These genetic variants have the potential to cause mild and moderate traits in the general population, as well as culminate in more severe phenotypes in clinical syndromes. In the present thesis, multiple approaches were applied to increase understanding about several aspects related to the 22q11.2 region. In the first study, we aimed to identify modifier CNVs, outside the 22q11.2 region, for congenital heart defects (CHD) in a cohort of 117 patients with the 22q11.2 deletion syndrome (22q11.2DS). After detection of CNVs using SNP-array methodology and quality control, 50 CNVs were identified in 38 patients. Genetic content of these CNVs and related biological pathways were examined and compared between patients with and without CHD. Genes affected by CNVs in CHD patients were enriched for several functional terms related to ubiquitination, transcription factor binding sites and miRNA targets, highlighting the complexity of the phenotype. Genes related to cardiac development and pathogenesis were identified in both groups of patients. These genes and the enriched pathways may indicate new cardiac phenotype modifiers in patients with 22q11.2DS. The second study presented the impact of 22q11.2 CNVs on different phenotypes was assessed in the UK Biobank population cohort (N = 405,324 subjects). First, Human Phenotype Ontology (HPO) terms linked to any of the 90 genes encompassed by the 22q11.2 region were mapped to 170 phenotypes from the UK Biobank. Then, the association between these traits and the copy-number state of the SNP-array probes present in the 22q11.2 region was evaluated. Significant associations were found for 17 phenotypes in different models, showing that duplications and deletions act on these traits differently. The causal effect of the expression level of 22q11.2 genes on the associated traits was evaluated using transcriptome-wide mendelian randomization (TWMR) approach, revealing the effect of ARVCF gene on body mass index and of DGCR6 gene on mean platelet volume. Furthermore, a multivariable mendelian randomization (MVMR) approach suggested a predominant role of horizontal pleiotropy for CNVs in the region. Together these studies provide new evidence to increase our understanding of the complex 22q11.2 region and the mechanisms involved in the clinical variability of the 22q11.2DS.
The 22q11.2 region is highly complex and predisposed to the occurrence of genomic rearrangements such as deletions and duplications. These genetic variants have the potential to cause mild and moderate traits in the general population, as well as culminate in more severe phenotypes in clinical syndromes. In the present thesis, multiple approaches were applied to increase understanding about several aspects related to the 22q11.2 region. In the first study, we aimed to identify modifier CNVs, outside the 22q11.2 region, for congenital heart defects (CHD) in a cohort of 117 patients with the 22q11.2 deletion syndrome (22q11.2DS). After detection of CNVs using SNP-array methodology and quality control, 50 CNVs were identified in 38 patients. Genetic content of these CNVs and related biological pathways were examined and compared between patients with and without CHD. Genes affected by CNVs in CHD patients were enriched for several functional terms related to ubiquitination, transcription factor binding sites and miRNA targets, highlighting the complexity of the phenotype. Genes related to cardiac development and pathogenesis were identified in both groups of patients. These genes and the enriched pathways may indicate new cardiac phenotype modifiers in patients with 22q11.2DS. The second study presented the impact of 22q11.2 CNVs on different phenotypes was assessed in the UK Biobank population cohort (N = 405,324 subjects). First, Human Phenotype Ontology (HPO) terms linked to any of the 90 genes encompassed by the 22q11.2 region were mapped to 170 phenotypes from the UK Biobank. Then, the association between these traits and the copy-number state of the SNP-array probes present in the 22q11.2 region was evaluated. Significant associations were found for 17 phenotypes in different models, showing that duplications and deletions act on these traits differently. The causal effect of the expression level of 22q11.2 genes on the associated traits was evaluated using transcriptome-wide mendelian randomization (TWMR) approach, revealing the effect of ARVCF gene on body mass index and of DGCR6 gene on mean platelet volume. Furthermore, a multivariable mendelian randomization (MVMR) approach suggested a predominant role of horizontal pleiotropy for CNVs in the region. Together these studies provide new evidence to increase our understanding of the complex 22q11.2 region and the mechanisms involved in the clinical variability of the 22q11.2DS.