Investigação de variantes genéticas em indivíduos com a síndrome da deleção 22q11.2 e seu efeito no fenótipo
Data
2022-09-15
Autores
Nunes Silva, Natalia Rodrigues 
Orientadores
Melaragno, Maria Isabel de Souza Aranha
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A síndrome de deleção 22q11.2 (SD22q11.2) resulta de deleções de segmentos
do cromossomo 22 em hemizigose, sendo a síndrome de microdeleção mais frequente
observada em humanos. Nossos estudos, assim como outros na literatura, indicam que
a síndrome de deleção 22q11.2 resulta em uma ampla variedade de sinais clínicos, como
malformações cardíacas congênitas, características faciais típicas, escoliose,
imunodeficiência e distúrbios psiquiátricos. Essa heterogeneidade fenotípica
apresentada pelos pacientes é observada até mesmo entre membros da mesma família.
Apesar de os genes sensíveis à dose localizados na região deletada serem os
principais candidatos ao fenótipo, os mecanismos moleculares envolvidos na etiologia
da variabilidade fenotípica da síndrome parecem ser mais complexos. Dessa maneira,
tem sido sugerido que modificadores genéticos, como as variantes de nucleotídeo único
(SNVs, do inglês, single nucleotide variants), fora da região deletada em 22q11.2,
poderiam modificar a expressividade do fenótipo.
Na presente tese, para uma melhor compreensão de modificadores genéticos
envolvidos na heterogeneidade fenotípica da SD22q11.2, foi desenhado um painel de
genes composto de nove genes candidatos para a SD22q11.2. Foram sequenciados 60
pacientes brasileiros com a SD22q11.2 e as variantes identificadas foram submetidas à
análise in silico que identificou seis variantes deletérias, sendo quatro SNVs e duas
indels. Essas variantes foram posteriormente associadas com as características clínicas
dos pacientes em que elas foram identificadas, corroborando seu possível papel como
modificadores genéticos. Ainda, de forma a se identificar variantes genéticas que
influenciam a expressividade de escoliose, característica frequente na SD22q11.2,
utilizamos summary statistics de GWAS já disponibilizados pela comunidade cientifica
para alimentar modelos de predição de escoliose na SD22q11.2. Também foi avaliado
o papel de variantes comuns para o fenótipo de escoliose na população em geral e o
papel de variantes associadas a alterações imunológicas não sindrômicas na etiologia da
escoliose idiopática. Os achados indicam que a escoliose idiopática compartilha
contexto genético com a doença inflamatória de Bowel e Chron, e que é possível
predizer a presença de escoliose na nossa coorte brasileira de 98 pacientes com a
SD22q11.2 por meio de modelos de aprendizado de máquina treinados em dados de
SNP-array de 2.966 pacientes com escoliose idiopática.
Dessa forma, foi possível a correlação dos dados obtidos com o fenótipo dos
pacientes de forma a se conhecer melhor os fatores genéticos envolvidos na
heterogeneidade clínica da SD22q11.2, e ainda, na escoliose idiopática na população em
geral
The 22q11.2 deletion syndrome (22q11.2 SD) results from deletions of chromosome 22 segments in hemizygous and is the most frequent microdeletion syndrome observed in humans. Our studies and others in the literature indicate that the 22q11.2 deletion syndrome results in a wide variety of clinical signs, such as congenital heart malformations, typical facial features, scoliosis, immunodeficiency, and psychiatric disorders. This phenotypic heterogeneity presented by patients is observed even among members of the same family. Although dose-sensitive genes located in the deleted region are the leading candidates for the phenotype, the molecular mechanisms involved in the etiology of the phenotypic variability of the syndrome appear to be more complex. Thus, it has been suggested that genetic modifiers, such as single nucleotide variants (SNVs), outside the deleted region in 22q11.2 could modify the expressiveness of the phenotype. In the present thesis, for a better understanding of genetic modifiers involved in the phenotypic heterogeneity of SD22q11.2, a gene panel composed of nine candidate genes for SD22q11.2 was designed. Sixty Brazilian patients with 22q11.2DS were sequenced, and the identified variants were submitted to in silico analysis, which identified six deleterious variants, four SNVs, and two indels. These variants were later associated with the clinical characteristics of the patients in which they were identified, corroborating their possible role as genetic modifiers. Also, to identify genetic variants that influence the expression of scoliosis, a frequent feature in SD22q11.2, we used GWAS summary statistics already made available by the scientific community to feed scoliosis prediction models in SD22q11.2. We also evaluated the role of common variants for the scoliosis phenotype in the general population and the role of variants associated with non-syndromic immunological changes in the etiology of idiopathic scoliosis. The findings indicate that idiopathic scoliosis shares a genetic context with inflammatory Bowel and Chron’s disease and that it is possible to predict the presence of scoliosis, as verified in our Brazilian cohort of 98 patients with 22q11.2DS using machine learning models trained on SNP-array data from 2,966 patients with idiopathic scoliosis. Thus, it was possible to correlate the data obtained with the patient's phenotype to better understand the genetic factors involved in the clinical heterogeneity of 22q11.2DS and in idiopathic scoliosis in the general population.
The 22q11.2 deletion syndrome (22q11.2 SD) results from deletions of chromosome 22 segments in hemizygous and is the most frequent microdeletion syndrome observed in humans. Our studies and others in the literature indicate that the 22q11.2 deletion syndrome results in a wide variety of clinical signs, such as congenital heart malformations, typical facial features, scoliosis, immunodeficiency, and psychiatric disorders. This phenotypic heterogeneity presented by patients is observed even among members of the same family. Although dose-sensitive genes located in the deleted region are the leading candidates for the phenotype, the molecular mechanisms involved in the etiology of the phenotypic variability of the syndrome appear to be more complex. Thus, it has been suggested that genetic modifiers, such as single nucleotide variants (SNVs), outside the deleted region in 22q11.2 could modify the expressiveness of the phenotype. In the present thesis, for a better understanding of genetic modifiers involved in the phenotypic heterogeneity of SD22q11.2, a gene panel composed of nine candidate genes for SD22q11.2 was designed. Sixty Brazilian patients with 22q11.2DS were sequenced, and the identified variants were submitted to in silico analysis, which identified six deleterious variants, four SNVs, and two indels. These variants were later associated with the clinical characteristics of the patients in which they were identified, corroborating their possible role as genetic modifiers. Also, to identify genetic variants that influence the expression of scoliosis, a frequent feature in SD22q11.2, we used GWAS summary statistics already made available by the scientific community to feed scoliosis prediction models in SD22q11.2. We also evaluated the role of common variants for the scoliosis phenotype in the general population and the role of variants associated with non-syndromic immunological changes in the etiology of idiopathic scoliosis. The findings indicate that idiopathic scoliosis shares a genetic context with inflammatory Bowel and Chron’s disease and that it is possible to predict the presence of scoliosis, as verified in our Brazilian cohort of 98 patients with 22q11.2DS using machine learning models trained on SNP-array data from 2,966 patients with idiopathic scoliosis. Thus, it was possible to correlate the data obtained with the patient's phenotype to better understand the genetic factors involved in the clinical heterogeneity of 22q11.2DS and in idiopathic scoliosis in the general population.