Submission Details

HNF1B was first reported in relation to autosomal dominant Renal Cysts and Diabetes Syndrome in 1997 (Horikawa et al., PMID: 9398836). An alternative description is Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) – HNF1B. This disease entity consistently includes a primary renal phenotype in which a wide variety of genitourinary developmental malformations may be present, such as renal cysts, interstitial fibrosis, absent or underdeveloped kidney, abnormal nephron development, hypoplastic glomeruli, enlarged renal pelvises, bicornuate uterus, atresia of the vas deferens, rudimentary uterus, vaginal aplasia. Diabetes is typically diagnosed in adolescence or young adulthood, but some families will have carriers who may not have been diagnosed with diabetes but will usually have some evidence of renal pathology that is either congenital or progressive. The disorder has also been referred to as maturity onset diabetes of the young 5 (MODY5) or HNF1B-MODY, as well as Renal Cysts and Diabetes (RCAD; MIM:137920). Treatment for diabetes often includes insulin but optimal management has not been established. Other variable features of the syndrome may include hypomagnesemia, hyperuricemia, pancreatic exocrine insufficiency, hepatic dysfunction such as cholestasis, and intellectual disability (possibly more often when caused by large deletion of 17q12).

Numerous variants have been reported in humans per ClinVar, especially whole gene deletions. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of case-level and experimental data: 18 points. Variants in this gene have been reported in at least 13 probands in 7 publications (PMIDS: 9398836, 12161522, 25705165, 25754277, 25441779, 15068978, 20378641). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function. This gene-disease association is supported by expression studies, animal models, and in vitro functional assays. In summary, HNF1B is definitively associated with autosomal dominant Renal Cysts and Diabetes Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes Gene Curation Expert Panel (12/10/2019) in collaboration with the ClinGen Kidney Cystic and Ciliopathy Disorders Gene Curation Expert Panel (1/19/2021) according to SOP Version 8.