Congenital split hand/split foot malformation (SHFM) is a complex congenital disorder with a highly variable clinical presentation and a poorly understood molecular basis, particularly associated with chromosome 10q24 microduplications. This review examines the genetic and molecular mechanisms underlying SHFM, with a focus on the role of microduplications in altering key genes such as FBXW4 and FGF8. It explores the integration of artificial intelligence (AI) in genomic data analysis, protein structure prediction, and protein-protein interaction modeling to enhance our understanding of the condition. Furthermore, the application of AI in optimizing smart biomaterials for personalized treatment strategies and gene editing technologies is discussed, offering novel approaches for regenerative repair. The review highlights how AI and advanced genomic tools can together provide new insights into SHFM's pathology, with potential for transformative clinical applications in diagnosis and treatment.