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Abstract: TH-PO373

Phenotypic Expression Among HNF1B Pathogenic Variant Carriers

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Fang, Brian, Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania, United States
  • Chang, Alex R., Geisinger Medical Center, Danville, Pennsylvania, United States
  • Mirshahi, Uyenlinh L., Geisinger Health, Danville, Pennsylvania, United States
  • Patel, Kashyap A., University of Exeter, Exeter, Devon, United Kingdom
  • Weedon, Michael, University of Exeter, Exeter, Devon, United Kingdom

Patients with HNF1B variants have shown variable phenotypic expression even between individuals with the same mutation between and within families. As most studies focus on patients with disease-specific cohorts, the phenotypic spectrum of HNF1B in the general population remains unclear.


We used data from 172,589 participants in the Geisinger MyCode/DiscoverEHR study, an unselected health system-based cohort with exome sequencing and EHR data. Variants were classified according to ACMG-AMP guidelines. Participants with pathogenic/likely pathogenic (P/LP) variants in HNF1B and 17q12 microdeletion were identified and were matched 1:1 by age decile, sex, and genetic ancestry with individuals without HNF1B pathogenic variants or 17q12 deletion (non-carriers). Patient medical records were examined to ascertain phenotypic features related to HNF1B clinical spectrum. Comparisons between individuals with and without HNF1B were made using Fisher exact test and t-tests.


There were a total of 25 participants with 17q12 microdeletion and 11 heterozygotes for P/LP single nucleotide variants (6 individuals with 5 protein truncating variants, 5 individuals with 4 missense variants). All 36 participants with HNF1B P/LP variants were matched 1:1 to 36 non-carriers. HNF1B pathogenic variants were associated with higher risk of diabetes (25% vs. 2.8%; p=0.01, any kidney/liver cyst ICD code 13.9% vs. 0%; p=0.05), hypomagnesemia <1.75 mg/dL (33% vs. 0%; p<0.001), and lower mean eGFR (67.4 vs. 88.2 ml/min/1.73m2;p=0.01). In focused chart review of the 36 carriers, 2 (5.6%) had end-stage kidney disease, and 22 (61.1%) had renal imaging, including 18 with computed tomography or magnetic resonance imaging of the abdomen. Of those with available imaging, 9/22 (40.9%) had bilateral renal cysts, 1/17 (6%) had liver cysts, 6/17 (35.3%) had atrophic or hypoplastic pancreas. Individuals with 17q12 microdeletion were more likely to have diabetes (40% vs. 9%; p=0.1) and bilateral renal cysts (among 22 with imaging: 8/12 [66.7%] vs. 1/10 [10%]; p=0.01) compared to those heterozygous for P/LP single nucleotide variants.


In an unselected health system-based cohort, we demonstrated variable penetrance and the wide spectrum of disease manifestations ranging from diabetes, renal cysts, and pancreatic abnormalities in patients with HNF1B pathogenic variants.