Abstract: PO1532
Identifying and Assessing the Phenotypic Features of HNF1B Deletions and Duplications in UK Biobank
Session Information
- Cystic Kidney Diseases: Mechanisms, Genetics, and Treatment
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Sukcharoen, Kittiya, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, United Kingdom
- Bingham, Coralie, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, United Kingdom
- Weedon, Michael, University of Exeter Medical School, Exeter, Devon, United Kingdom
- Oram, Richard A., University of Exeter Medical School, Exeter, Devon, United Kingdom
Group or Team Name
- University of Exeter
Background
Heterozygous mutations of hepatocyte nuclear factor 1β (HNF1B) are the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature. Other features include early-onset diabetes and abnormal liver function. It is thought that duplications of HNF1B do not result in strong phenotypic features.
The true pathogenicity and penetrance of many rare putative disease-causing copy number variants (CNVs) is uncertain and may be over-estimated by clinical ascertainment.
We aimed to assess the pathogenicity and penetrance of HNF1B deletions and duplications in UK Biobank (UKBB) and to describe any associated phenotype.
Methods
We used data from 388,714 UKBB participants to assess CNVs of HNF1B in a population-based setting using SNP chip intensity data. We tested the association of these CNVs with diabetes and other clinically-relevant traits. We assessed the UKBB phenotype and biomarker information and correlated these with the deletions and duplications.
Results
We identified 11 individuals with large deletions relating to HNF1B and 106 with duplications. There were no significant difference in the average ages of deletion (53), duplication (56) and UKBB population (57). Of the 11, 3 were reported to have glomerular disease, 1 had haematuria, 1 had a renal transplant, and 6 had diabetes (55% vs. 5% amongst the rest of UKBB; P=2x10-6). The penetrance of diabetes was 30% and average eGFR was 71 (45% with eGFR<60) compared to average GFR 91(p<0.0001) in UKBB population. Their liver function is comparatively different. Gamma GT 110 v 37.4 (p<0.0001) and ALP 186.5 v 83.5 (p<0.0001) in UKBB population.
Average eGFR was lower in people with a duplication (80 v 91 in UKBB population, p<0.0001). We found no association between HNF1B duplication and diabetes (4.4% vs. 5.3%; P=0.8) or liver function.
Conclusion
HNF1B deletions and duplications can be detected in a large unselected dataset. Deletions are more pathogenic than duplications. However, HHF1B duplications do appear to affect renal function, which has not been previously described. The frequency of both HNF1B deletions and duplications may be higher than previously estimated.