Hepatocyte nuclear factor-1β gene deletions -: a common cause of renal disease

Background. Hepatocyte nuclear factor-1 beta (HNF-1 beta) is a critical transcription factor in pancreatic and renal development. Our previous report identified HNF-1 mutations in 23/160 patients with unexplained renal disease. The most common phenotype is renal cysts, which is frequently associated with early-onset diabetes in the renal cysts and diabetes (RCAD) syndrome. HNF-1 beta gene deletions have recently been shown to cause renal malformations and early-onset diabetes. Methods. We developed a multiplex ligation-dependent probe amplification (MLPA) assay for HNF-1 beta gene dosage analysis and tested patients with unexplained renal disease in whom mutations had not been found by sequencing. Results. Whole HNF-1 beta gene deletions were detected in 15/133 probands. Renal cysts were present in 13/15, including three with glomerulocystic kidney disease and one with cystic renal dysplasia. Renal function ranged from normal to transplantation aged 3 years. Ten probands had diabetes (nine having RCAD). In addition, four had abnormal liver function tests, two showed pancreatic atrophy and 3/10 female probands had uterine malformations. Whole HNF-1 beta gene deletions are a common cause of developmental renal disease, particularly renal cystic disease with or without diabetes. Conclusions. The phenotype associated with deletions or coding region/splicing mutations is very similar suggesting that haploinsufficiency is the underlying mechanism. Patients with features suggestive of the HNF-1 beta clinical phenotype should be tested for mutations both by sequence and dosage analysis.