Genotype-phenotype correlations in HNF1B-associated disease: a systematic review

Multiple organ systems can be affected by pathogenic variants in the HNF1B gene, with renal phenotype usually being the initial presentation. However, the genotype-phenotype correlations in HNF1B -associated disease remain unclear. To further explore the genotype-phenotype correlations and potential ethnic-specific effects in HNF1B -associated disease, a systematic review of published literature was conducted in our research. Our findings indicated that patients with whole-gene deletion exhibited relatively better renal outcomes but a higher predisposition to neuropsychiatric disorders. Compared to patients with non-truncating mutations, those with truncating mutations were more prone to renal cysts, hypomagnesemia and hyperuricemia but less likely to develop diabetes. Among truncating mutations, splice-site mutations were associated with a reduced risk of renal cysts. Mutations within the DNA-binding domain exhibited more severe renal and extrarenal phenotypes. Compared to those with mutations within the POU homeodomain (POUh), patients with mutations in the POU-specific domain (POUs) exhibited poorer renal outcomes. Besides, ethnicity appeared to influence genotype-phenotype correlations. In European populations, POUs domain mutations conferred a worse renal prognosis than POUh domain mutations, which was not observed in Asian populations. Asian patients with whole-gene deletion or truncating mutations showed a higher susceptibility to liver dysfunction, whereas European patients with POUs domain mutations exhibited increased risk. In summary, Our study identified potential genotype-phenotype correlations in HNF1B -associated disease based on pooled published data, informing risk prediction and warranting validation in future studies. Clinical trial number : Not applicable.