Genetic variants in HNF1B encoding the transcription factor hepatocyte nuclear factor-1 beta (HNF-1B) cause Maturity-Onset Diabetes of the Young type 5 (MODY5; HNF1B-MODY) and are the most common known monogenic cause of developmental kidney disease. The aim of this study was to assess pathogenicity of HNF1B variants identified among 312 patients suspected of monogenic diabetes from the Personalized Diabetes Medicine Program (PDMP) at the University of Maryland. Patients suspected of monogenic diabetes underwent next generation sequencing for 40 genes, including HNF1B. Variants were classified according to ACMG/AMP variant interpretation guidelines. To investigate the effect of HNF1B variants on normal HNF-1B transcriptional activity, we used a Dual-Luciferase assay system in transfected HeLa cells. DNA-binding ability was studied by EMSA and protein localization was determined by fractionation and confocal microscopy. Seven HNF1B variants were identified in 7 unrelated individuals. One variant (p.H336Pfs*22) was classified as pathogenic, 5 (p.T88A, p.A167P, p.N394D, p.V458G, p.T544A) as unknown significance (VUS) and 1 variant as benign (p.D82N). Two variants, p.A167P and p.H336Pfs*22, inferred severely reduced transactivation potential (25% and 34% of WT, respectively). In addition, p.A167P demonstrated decreased protein expression (26% of WT) and a significant loss in DNA binding ability (19% of WT). The p.H336Pfs*22 variant carrier has renal agenesis, often associated with HNF1B mutations, while the p.A167P carrier lacks extra-pancreatic features. The functional evidence allowed p.A167P to be reclassified as likely pathogenic when added to existing evidence (computationally predicted deleteriousness and absence from population databases). Obtaining functional data can improve variant interpretation and enable a more precise diagnosis in patients carrying an HNF1B variant.
B.B. Johansson: None. A. Pavithram: None. H. Zhang: None. K.A. Maloney: None. M. Ringdal: None. A. Kaci: None. J.V. Sagen: Other Relationship; Self; Novo Nordisk A/S. J. Kleinberger: None. L. Jeng: None. P. Njølstad: None. T.I. Pollin: None. J. Molnes: None.
Western Norway Regional Health Authority; University of Bergen; Norwegian Diabetes Foundation