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Background: Homozygous mutations in the transcription factor RFX6 are the cause of the Mitchell-Riley syndrome (MRS) associating neonatal diabetes, congenital digestive system, such as biliary atresia, pancreatic hypoplasia, duodenal and/or jejunal atresia, intestinal malrotation, gallbladder aplasia, cholestasis. A constitutive inactivation of RFX6 leads also to gastric heterotopia. Application of RNA-seq in human diseases may help to better understand pathogenic mechanism of diseases and to predict the risk of developing chronic disorders and personalizing their prevention and treatment. We evaluated oncogenic patterns and cancer predisposition using the transcriptomic profile in a case of MRS with neonatal diabetes, duodenal atresia, and extensive intestinal tract gastric heterotopia., Results: We signalled the interactors of RFX6 with other up and downregulated genes, that may be interested in severity of diabetic condition, in multi-organs impairment and cancer predisposition. Furthermore, several dysregulated genes are involved in biological processes that can lead to promote cancer including "Evading apoptosis" (BAD, BBC3, EGF, FGFR2, FLT3LG, HMOX1, HRAS, IFNAR2, IGF1R, IL12RB1, IL13RA1, IL15, IL2RB, IL2RG, IL6R, KEAP1, MGST1, PDGFA, PDGFRB, PIK3R3, RALB, RALGDS, RASSF1, SOS1, TGFA, TXNRD3), "Proliferation" (APC, BRAF, CCND2, CCND3, CCNE2, FGFR2, FLT3LG, FZD1, FZD6, HMOX1, HRAS, IGF1R, KEAP1, LRP6, MAPK3, MGST1, PDGFA, PDGFB, PDGFRB, RB1, SOS1, TGFA, TXNRD3, WNT10B), "Sustained angiogenesis" (BRAF, FGFR2, FLT3LG, HRAS, IGF1R, JAG1, MAPK3, NOTCH2, PDGFA, PDGFB, PDGFRB, SOS1, TGFA, TGFB1), "Genomic instability" (BAD, BBC3) and "Insensitivity to anti-growth signals" (SMAD2, TGFB1). We also inspected the signalings and their related genes in cancer, such as "PI3K signaling", "ERK signaling", "JAK-STAT signaling", "Calcium signaling", "Other RAS signaling", "WNT signaling"., Conclusions: In our MRS patient, we signaled the interactors of RFX6 with other up- and downregulated genes that may be related to severe diabetic condition, multi-organ impairment, and cancer predisposition. Notably, many dysregulated genes may lead to triggering carcinogenesis. The possibility of the patient developing cancer degeneration in heterotopic gastric mucosa and/or additional long-term tumoral sequelae is not excluded. Personalized prevention and treatment strategies should be proposed., (© 2021. The Author(s).)