Etiological investigation in patients with phenotypic alterations and balanced chromosomal rearrangements

• Grant number: 24/18075-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: June 01, 2025
• End date: March 31, 2030
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Isabel de Souza Aranha Melaragno
• Grantee: Michael Wendel da Silva
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/21644-0 - Impact of genetic variants on genomic stability and their effects on the phenotype, AP.TEM

Abstract

Among individuals with balanced chromosomal rearrangements, which do not involve a gain or loss of genetic material, approximately 6% exhibit phenotypic abnormalities. These abnormalities can be attributed to various pathogenic mechanisms, such as copy number variations (CNVs) not detected by karyotyping, gene disruptions, gene fusions, position effects, as well as alterations in topologically associated domains (TADs) and genomic interactions. Alternatively, chromosomal rearrangement may represent a casual association, with no impact on the phenotype. This project aims to investigate and characterize the pathogenic mechanisms in patients with phenotypic alterations and balanced chromosomal rearrangements. Patients will undergo a detailed clinical evaluation and be subjected to various diagnostic approaches. Initially, chromosomal microarray analysis will be performed to study CNVs. Optical genome mapping (OGM) and Sanger sequencing of the breakpoints will be used to investigate gene disruptions and fusions. In silico analysis of altered TADs and gene and protein interactions will be carried out using OGM and Sanger sequencing data. In cases in which no diagnostic etiology is identified, whole-genome sequencing will be performed. Additionally, all patients will have genotype-phenotype correlations studied. The results of this research are expected to improve clinical management and prognosis of patients, as well as expand knowledge about balanced chromosomal rearrangements. (AU)