Genetic Variability of iPitx2/i Exon 4 in Senegalese Patients with Rheumatic Mitral Valve Disease with and Without Atrial Fibrillation: A Prospective Study with in Silico Analysis

Introduction: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with significant morbidity and mortality. In sub-Saharan Africa, AF frequently occurs at a younger age, most often in the context of rheumatic mitral valve disease (RMVD), and is characterized by advanced atrial remodeling. Genetic studies have identified the Paired-like Homeodomain Transcription Factor 2 (iPITX2/i) gene at the 4q25 locus as a major susceptibility factor for AF. Objective: to investigate genetic variability within exon 4 of the iPITX2/i gene in African patients with RMVD and to explore its potential role in AF susceptibility. Materials and Methods: this prospective observational study was conducted at the Cuomo Cardiac Surgery Center, Aristide Le Dantec University Hospital (Dakar, Senegal). Forty-five patients undergoing surgery for RMVD were included, along with 15 control subjects without documented AF. Intraoperative left atrial endocardial biopsies were obtained in operated patients. Genomic Deoxyribonucleic Acid (DNA) extracted from atrial tissue and control blood samples was used for targeted amplification and Sanger sequencing of exon 4 of iPITX2/i. Identified variants were annotated using public databases and evaluated with in silico prediction tools. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: the study population was young (mean age 31 years) and predominantly female. AF was present in 56% of patients and was associated with marked left atrial dilatation and preserved left ventricular systolic function. Sequencing identified four rare missense variants (c.59CT, c.97AG, c.121CG, and c.149GT) located within the conserved homeobox domain of iPITX2/i. All variants were heterozygous and showed extremely low allele frequencies in population databases. In silico predictions were heterogeneous, and all variants were classified as variants of uncertain significance. Genetic diversity analyses revealed slightly higher haplotype and nucleotide diversity in AF patients, without significant genetic differentiation between groups. Conclusion: rare variants in exon 4 of iPITX2/i were identified in African patients with RMVD. Although their functional significance remains uncertain, these findings support a potential modulatory role of iPITX2/i in susceptibility to atrial fibrillation and highlight the importance of genetic studies in underrepresented African populations.