Core Viewpoint - The research identifies HMGN1 gene on chromosome 21 as a key factor mediating myocardial reprogramming, leading to congenital heart defects in patients with Down syndrome [3][5]. Group 1: Research Findings - Down syndrome occurs in approximately 1 in every 700 live births, with an increased incidence related to maternal age [2]. - About 50% of Down syndrome patients exhibit congenital heart defects, with atrioventricular canal (AVC) defects being the most common, occurring at a rate approximately 1000 times higher than in the general population [2]. - The study published in Nature reveals that increased copy number of the HMGN1 gene is responsible for heart defects in Down syndrome patients [3][5]. Group 2: Methodology - The research utilized human pluripotent stem cells (hPSCs) and a Down syndrome mouse model to identify HMGN1 as a critical factor for these defects [5]. - Single-cell transcriptomics indicated that Down syndrome causes a transition of human epicardial cells to a ventricular myocardium state [5]. - CRISPR activation combined with single-cell RNA sequencing (CROP-seq) demonstrated that upregulation of HMGN1 mimics this transition, while deletion of one HMGN1 allele in trisomy 21 cells restores normal expression [5]. Group 3: Implications - Reducing Hmgn1 dosage in the Down syndrome mouse model can restore transcriptional changes in AVC myocardial cells, thereby repairing heart valve septal defects [7]. - HMGN1 is highlighted as a dosage-sensitive regulatory factor in the development of AVC and cardiac septum formation in Down syndrome patients [8]. - The study serves as a model for using homologous gene systems to dissect the pathogenesis of aneuploidy-related diseases and locate pathogenic genes within complex genetic syndromes [8].