#1165 HNF1B genotype-phenotype correlation in renal patients from Galicia

Abstract Background and Aims The HNF1B gene encodes a transcription factor that regulates gene expression in various tissues, including pancreatic beta-cells, kidneys, liver, intestines, and neurons, playing crucial roles during embryonic and postnatal development. Genes regulated by Hnf1b are involved in key processes such as nephrogenesis, ion transport, cellular polarity, tight junctions, primary cilia development, and renal metabolism. Consequently, pathogenic alterations in HNF1B disrupt its molecular functions, leading to a broad spectrum of renal and extrarenal manifestations. Patients with HNF1B alterations are categorized into three groups based on the type of genetic alteration: (1) 17q12 microdeletion carriers; (2) truncating point mutation carriers; and (3) missense point mutation carriers. Our group has established a large cohort of renal patients with suspected hereditary kidney disease, predominantly from Galicia (approximately 76%), a region in western Europe characterized by unique geographical, ethnic, and consanguinity patterns. These factors enhance the genetic value of this population for genotype-phenotype correlation studies. This study aims to establish genotype-phenotype correlations for HNF1B variants in a Galician cohort. Method This retrospective, observational, multicenter study analyzed a large cohort of patients with suspected hereditary kidney diseases enriched in the Galician population. Genetic studies were performed using Next-Generation Sequencing (NGS) and/or Sanger sequencing. Patients carrying HNF1B alterations were selected from this cohort. A total of 31 subjects (27 probands and 4 relatives) were included, and detailed clinical data were collected and analyzed. Results Among probands, 55.55% carried the 17q12 microdeletion, 18.52% carried truncating alterations, and 25.93% exhibited missense alterations. Over 60% of probands presented with hyperechogenicity, renal cysts, and/or hypomagnesemia. Additional observed manifestations included hyperuricemia, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), diabetes/ Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, as well as pancreatic, hepatic and psychiatric/neurological anomalies. Distinct trends were observed across the three alteration groups for clinical features such as renal cysts, initial clinical suspicion, hyperuricemia, and hypomagnesemia. Conclusion This study highlights the broad and variable multi-systemic manifestations associated with HNF1B alterations and provides valuable insights into genotype-phenotype correlations. Proving that accurate genetic diagnosis is essential for providing personalized genetic counseling and implementing appropriate follow-up care based on the specific mutation type.