HNF1B-related disease: developmental origins, molecular mechanisms, and multisystem clinical challenges

Variants or deletions involving the HNF1B gene cause HNF1B-MODY. HNF1B-MODY represents a multisystem disorder extending far beyond its original classification as a monogenic form of diabetes. HNF1B's role in human development includes critical involvement in the organogenesis of the kidney, pancreas, liver, genitourinary tract, and nervous system. Approximately half of affected individuals carry large 17q12 deletions encompassing HNF1B and neighboring genes, correlating with broader syndromic features such as intellectual disability, autism spectrum traits, and psychiatric illness. The increasing availability of next-generation sequencing, coupled with copy number variant analysis, has improved diagnostic yield. Underdiagnosis remains common due to variable expressivity and phenotypic overlap with more prevalent disorders. Notable progress has been made in dissecting tissue-specific roles of HNF1B. Patient-derived iPSC models and single-cell transcriptomics offer new insights into early developmental pathways and transcriptional networks. These tools enable organoid-based studies and the potential discovery of therapeutics. Clinically, awareness of symptoms, such as renal cysts, persistent hypomagnesemia, pancreatic hypoplasia, and non-autoimmune diabetes, has led to the development of diagnostic scoring systems and multidisciplinary care algorithms. Although current treatment remains supportive, research into gene regulation, epigenetic modifiers, and pharmacologic rescue strategies is ongoing. HNF1B-related disease illustrates how pleiotropic gene dysfunction can present with diverse organ involvement. Integrating genomics, developmental biology, and targeted surveillance may help improve early diagnosis and patient outcomes.