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Abstract: FR-PO971

The Exhaustive Screening Tool Is Superior to the Simplified Version to Identify Pediatric Patients with a Pathogenic HNF1β Genotype

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Downie, Mallory Lorraine, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Jobling, Rebekah, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Jawa, Natasha, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Noone, Damien Gerard, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Lemaire, Mathieu, Hospital for Sick Children, Toronto, Ontario, Canada

Pathogenic genotypes involving hepatocyte nuclear factor-1 beta (HNF1β) are now recognized as the most frequent cause of monogenic congenital anomalies of the kidney and urinary tract (CAKUT), a leading cause of paediatric-onset chronic kidney disease (CKD). Identifying these patients is challenging due to the substantial phenotypic heterogeneity across age groups. We sought to characterize the paediatric phenotype of HNF1β disease and to assess the utility of established screening tools (exhaustive or simplified) for pediatric patients with renal cysts.


Between 2011 and 2018, 45 patients with renal cysts from our institution were tested for mutations in the gene HNF1β.


Testing was positive in 17/39 (44%) unrelated kindreds (total, 21/45 patients) with median age at diagnosis of 6.1 years (range 0.1-17.3). A heterozygous deletion encompassing the entire HNF1β gene was detected in all but 2/17 kindreds that had either a gene duplication or a point mutation, respectively. Analysis of the three multiplex kindreds revealed significant intrafamilial phenotypic heterogeneity. The most common clinical features included hypomagnesemia (53%, 9/17), neurodevelopmental problems (43%, 9/21), hyperuricemia (50%, 4/8), hyperparathyroidism (33%, 3/9), and pancreatic hypoplasia (14%, 3/21). Clinical features commonly reported in adults were rare: no patients with hypokalemia or early-onset gout, and two patients with either maturity-onset diabetes of the young (MODY) or unexplained elevated liver enzymes. The exhaustive screening tool identified all affected patients but required testing 80% of the patients who tested negative (19/24). In contrast, the simplified screening tool called for genetic testing for only 4/45 patients, all of whom ultimately tested positive.


We observed that patients harboring a HNF1β mutation display variable phenotypic penetrance and expressivity. This heterogeneity was even noted among members of multiplex kindreds. A comparison of the simplified and exhaustive screening tools applied to pediatric patients with renal cysts reveals that the latter is more sensitive to identify patients with pathogenic HNF1β genotypes.