Kidney International Reports (Aug 2024)

Renal and Extrarenal Phenotypes in Patients With HNF1B Variants and Chromosome 17q12 Microdeletions

  • Bénédicte Buffin-Meyer,
  • Juliette Richard,
  • Vincent Guigonis,
  • Stefanie Weber,
  • Jens König,
  • Laurence Heidet,
  • Nabila Moussaoui,
  • Jeanne-Pierrette Vu,
  • Stanislas Faguer,
  • Audrey Casemayou,
  • Richa Prakash,
  • Véronique Baudouin,
  • Julien Hogan,
  • Demi Alexandrou,
  • Detlef Bockenhauer,
  • Justine Bacchetta,
  • Bruno Ranchin,
  • Stepanka Pruhova,
  • Jakub Zieg,
  • Annie Lahoche,
  • Christine Okorn,
  • Violetta Antal-Kónya,
  • Denis Morin,
  • Francesca Becherucci,
  • Sandra Habbig,
  • Max C. Liebau,
  • Mathilde Mauras,
  • Tom Nijenhuis,
  • Brigitte Llanas,
  • Djalila Mekahli,
  • Julia Thumfart,
  • Burkhard Tönshoff,
  • Laura Massella,
  • Philippe Eckart,
  • Sylvie Cloarec,
  • Alejandro Cruz,
  • Ludwig Patzer,
  • Gwenaelle Roussey,
  • Isabelle Vrillon,
  • Olivier Dunand,
  • Lucie Bessenay,
  • Francesca Taroni,
  • Marcin Zaniew,
  • Ferielle Louillet,
  • Carsten Bergmann,
  • Franz Schaefer,
  • Albertien M. van Eerde,
  • Joost P. Schanstra,
  • Stéphane Decramer,
  • Gema Ariceta, MD, PhD,
  • Elisa Benetti, MD, PhD,
  • Marcus R. Benz, MD,
  • Anna Bjerre, MD, PhD,
  • Bernard R. Boudailliez, MD,
  • Antonia Bouts, MD, PhD,
  • Jens Drube,
  • Ann Christin Gjerstad, MD, PhD,
  • Augustina Jankauskiene, MD, PhD,
  • Eszter Jávorszky, PhD,
  • Nadine Jay, MD,
  • Martin Kirschstein, MD, PhD,
  • Nataša Marčun Varda, MD, PhD,
  • Olivier Niel, MD, PhD,
  • François Nobili, MD,
  • Christine Pietrement, MD, PhD,
  • Dovile Ruzgiene, MD,
  • Raphael Schild, MD,
  • Hagen Staude, MD,
  • Kálmán Tory, MD, PhD,
  • Michel Tsimaratos, MD, PhD,
  • Ulrike Walden, MD,
  • Hildegard Zappel, MD

DOI
https://doi.org/10.1016/j.ekir.2024.05.007
Journal volume & issue
Vol. 9, no. 8
pp. 2514 – 2526

Abstract

Read online

Introduction: Hepatocyte nuclear factor 1-beta (HNF1B) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease. Methods: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype (HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia. Results: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19–0.44, P < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POUh) DNA-binding and transactivation domains rather than the POU-specific domain (POUs) DNA-binding domain (HR: 0.15 [95% CI: 0.06–0.37), P < 0.001 and HR: 0.25 (95% CI: 0.11–0.57), P = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia. Conclusion: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POUs DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling.

Keywords