RFX6 is a transcription factor essential for endocrine pancreas development and islet cell function. It directs differentiation of four of five islet cell types and is required for insulin production, acting downstream of NEUROG3 to regulate beta-cell maturation genes by forming heterodimers with RFX3 and binding X-box promoter elements. RFX6 also promotes glucose-stimulated insulin secretion by activating insulin and L-type calcium channel genes and maintains adult alpha-cell function by regulating genes governing nutrient sensing, hormone processing, and glucagon secretion 1. In disease contexts, RFX6 variants cause distinct pathological outcomes. Homozygous loss-of-function mutations cause Mitchell-Riley syndrome, characterized by neonatal diabetes with pancreatic hypoplasia and intestinal atresia through increased endocrine progenitor apoptosis and downregulation of endocrine differentiation genes 2. Heterozygous carriers of the Finnish-enriched p.His293LeufsTer7 variant (approximately 1:250 carriers) exhibit RFX6 haploinsufficiency, resulting in impaired beta-cell maturation, altered calcium signaling, and reduced insulin secretion without affecting beta-cell number, predisposing to type 2 and gestational diabetes 3. Recent evidence indicates that in early-stage type 2 diabetes, genetic risk converges on RFX6-mediated regulatory networks to reduce insulin secretion, with RFX6 identified as a hub gene within beta-cell gene regulatory modules 4. RFX6 also regulates intestinal patterning upstream of PDX1 and coordinates early gastrointestinal tract regional identity 5.