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Investigation of genetic variants in individuals with 22q11.2 Deletion Syndrome and its effect on phenotype

Grant number: 20/04414-8
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): October 01, 2020
Effective date (End): September 30, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Maria Isabel de Souza Aranha Melaragno
Grantee:Natália Rodrigues Nunes Nishimoto
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated scholarship(s):20/14411-6 - Investigation of genetic modifiers in individuals with the 22q11.2 deletion syndrome and its relationship with the disease phenotype, BE.EP.DD


The 22q11.2 Deletion Syndrome (22q11.2DS) results from the loss of chromosome 22 DNA segments and is the most frequent of microdeletion syndromes. The 22q11.2 region involved in the deletion is quite complex and contains highly repetitive Low Copy Repeats (LCR), DNA sequences that make the region susceptible to recurrent genomic rearrangements. Our studies, as well as others in the literature, indicate that 22q11.2 Deletion Syndrome results in a wide variety of often different clinical signs. A phenotype of considerable clinical relevance in 22q11.2DS is scoliosis, which affects about 50% of patients. The scoliosis present in 22q11.2DS is clinically similar to idiopathic scoliosis (isolated), and it has been suggested that both have common causal pathways. A relationship between idiopathic scoliosis and Congenital Heart Disease (CHD) is indicated in the literature, with CHD also being a relevant clinical feature for 22q11.2DS. Recently, a study had results that showed that the 22q11.2 deletion was associated with an increased risk of developing scoliosis in a CHD sample, these findings suggest that the 22q11.2 deletion may represent a common genetic pathway for the development of CHD and scoliosis. Different factors have been pointed out and explored by our research group for a better understanding of the phenotypic heterogenicity of the syndrome. It has been suggested that genetic modifiers, such as Copy Number Variation (CNVs) or Single Nucleotide Variants (SNVs) outside the deleted region at 22q11.2, could modify the expressivity of the phenotype. For example, it has been observed by Dantas et al. (2 019) that, in addition to reduced expression of genes in hemizygosity, there is also a reduction of expression in genes with a normal number of copies near the deleted region. It is indicating a possible role of these genes in phenotypic signs of the syndrome. In the present project, we aim to correlate the data obtained with the patients' phenotypes in order to understand better the genetic factors involved in the clinical heterogeneity of 22q11.2DS. Computational analyzes will be performed based on data from the sequencing of a candidate genes panel for phenotypic variability in the syndrome. The role of genetic variants, their impact on mRNA expression, their involvement with mRNA-miRNA interactions, and the relationship of these changes to the phenotype presented by patients will be evaluated. Besides, machine learning models will be applied, especially for the risk of scoliosis, based on large-scale genomic data generated by the SNP-array technique of our Brazilian 22q11.2DS cohort. Hence, it will be possible to clarify the role of modifiers in the scoliosis phenotype in 22q11.2DS and may identify genetic factors outside the region deleted in 22q11.2DS that can help in elucidating the etiology of idiopathic scoliosis, present in the general population. The results obtained with this study will allow a better understanding of the mechanism of genetic modifiers involved in the expressivity of the phenotype in the 22q11.2DS. The syndrome has many phenotypes in which this machine learning approach can be applied to others in the future. (AU)

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