The molecular basis, involving mutations in six key genes (ARHGAP31, RBPJ, NOTCH1, DLL4, DOCK6, and EOGT) that disrupt critical cellular pathways including Notch signaling and Cdc42/Rac1-mediated cytoskeletal regulation, explains the wide phenotypic variability, from aplasia cutis congenita and limb defects to severe cardiovascular and neurological anomalies. This evidence concerns the gene ARHGAP31 and aplasia cutis congenita.