Xia-Gibbs syndrome: molecular and clinical characterization of a series of Brazilian cases and establishment of induced pluripotent stem cells (iPSC) lines

Abstract

Xia-Gibbs syndrome (XGS) is a syndromic form of intellectual disability with dominant autosomal inheritance, caused by de novo pathogenic variants of the AHDC1 gene. It was first described in 2014 and has few reported cases with several different variants, reflecting the extensive clinical variability of the syndrome. Additionally, most of the syndrome's pathological mechanisms are still unknown. To study XGS, we have established a cellular model using cells from three individuals (already characterized induced pluripotent stem cell lines - iPSC) and an animal model (zebrafish - under characterization). This project is an extension of our previous study on XGS, with the main goals of molecular and clinical characterization of a large group of Brazilian patients and the establishment of new iPSC lines. The main objectives are (1) Collect and describe clinical and molecular data of XGS patients to outline the clinical manifestation spectrum and evaluate genotypic-phenotypic relations present in the syndrome; (2) Isolate peripheral blood mononuclear cells (PBMC) from the patients; (3) Reprogram PBMC to establish iPSC lines from a minimum of two patients. If possible, apply characterization of the pluripotent phenotypic and quality tests during this project phase; (4) Investigate the presence of transcripts with pathogenic variants in AHDC1 in mRNA extracted from iPSC lines to verify the mRNA escape decay mediated by nonsense mutations. Due to the condition's rarity, phenotypic and molecular variability, and poorly comprehended pathophysiological mechanisms, this study is important in increasing knowledge about the syndrome and maximizing the results obtained in our previous study.