Decoding trisomy 21: organelle pathology and molecular cascades in heart defects

Down syndrome (DS), the most common chromosomal abnormality associated with moderate to severe intellectual disability and often accompanied by congenital heart defects (CHDs), is reviewed in this article. Approximately half of all patients with DS exhibit a spectrum of CHDs, among which atrioventricular septal defects (AVSDs) are the most common. The article explores the molecular and subcellular mechanisms involved in cardiovascular pathology in DS, with an emphasis on the role of altered gene expression beyond the trisomy of chromosome 21. It was found that the cardiac development and function were affected by various protein-coding genes (DSCAM, RCAN1, DYRK1A) and non-coding RNAs. In addition, the calcineurin/NFAT and D-cyclin/Rb/E2F signaling pathways were impacted. The article indicates that although DS patients typically present with CHDs, they exhibit less frequently cardiac hypertrophy and ischemic heart disease than those without DS. Moreover, mitochondrial dysfunction characterized by abnormal morphology and reduced oxygen consumption and the impaired function of lysosomes and autophagy are involved in the pathogenesis of CHD in DS. The article discusses the unique aspects of cardiovascular disease in DS based on studies employing human fetal and induced pluripotent stem cells and mice with trisomy 21. It was concluded that the development of CHDs in DS is complex and involves multiple mechanisms, including gene dosage effects, aberrant signaling pathways, non-coding RNAs, and dysfunctional organelles. The study highlights areas of research with the potential to yield novel therapeutic interventions for CHDs in patients with DS and contribute to a better understanding of cardiovascular pathology in general. (Figure 1)