GENOMIC AND FUNCTIONAL STUDY OF SYNDROMIC FORMS OF INTELLECTUAL DISABILITY

• Grant number: 22/03980-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): February 01, 2023
• Effective date (End): January 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Ana Cristina Victorino Krepischi
• Grantee: Laura Machado Lara Carvalho
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID

Abstract

About 1% of the world's population has intellectual disability (ID), a condition that results in an important socioeconomic impact. ID is characterized by reduced ability to understand new information, learn skills and develop basic activities autonomy. When other phenotypes occur simultaneously, ID is classified as syndromic, which is often monogenic in origin. There are still gaps in the knowledge regarding the molecular basis of monogenic ID, and up to 50% of patients remain without a molecular diagnosis. In particular, it is estimated that the majority of genes related to autosomal recessive ID (ARID) has not yet been identified. Genetic diagnosis is essential both for proper clinical management and to elucidate mechanisms that modulate cognitive abilities, opening up the way to develop future therapeutic interventions. The main objective of this study is the genomic and functional investigation of ID syndromic forms. We intend to uncover novel candidate genes for ARID, by analyzing the exome data of 33 individuals with syndromic ID who have consanguineous parents (ARID hypothesis). We will also develop a model of cortical neurons to evaluate biallelic mutations in EHMT2 (ARID candidate gene) and to investigate pathophysiological mechanisms of Xia-Gibbs syndrome (XGS), using as models with mutations in AHDC1 human cortical neurons and zebrafish. PARTIAL RESULTS: The ARID cohort exome data were previously obtained, and their analysis is in progress by the researcher. A case report of a patient with mutation in SCAF4 gene, recently described in association with syndromic ID, has already been submitted for publication. Additionally, in this analysis we identified the EHMT2 gene as a new candidate for ARID, and PBMCs (peripheral blood mononuclear cells) of the family were collected for reprogramming into iPS (induced pluripotent stem cells). In the case of XGS, the animal (zebrafish) and cell models with mutations in AHDC1 were developed by the candidate during her doctorate (FAPESP scholarship 2018/08486-3, supervised by Dr. Carla Rosenberg) and will be characterized.