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 Böckenhauer, Justine Bacchetta, Bruno Ranchin, Štěpánka Průhová, 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 Francisco‐Cruz, Ludwig Patzer, G. Roussey, Isabelle Vrillon, Olivier Dunand, Lucie Bessenay, Francesca Taroni, Marcin Zaniew, Férielle Louillet, Carsten Bergmann, Franz Schaefer, Albertien M. van Eerde, Joost P. Schanstra, Stéphane Decramer, Gema Ariceta, Elisa Benetti, Marcus R. Benz, Anna Bjerre, B. Boudailliez, Antonia Bouts, Jens Drube, Ann Christin Gjerstad, Augustina Jankauskiene, Eszter Jávorszky, Nadine Jay, Martin Kirschstein, Nataša Marčun Varda, Olivier Niel, François Nobili, Christine Piétrement, Dovilė Ruzgienė, Raphael Schild, Hagen Staude, Kálmán Tory, Michel Tsimaratos, Ulrike Walden, H. Zappel
Abstract
IntroductionHepatocyte 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.MethodsThis was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European ERKNet-ERN network 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 (eGFR < 60 mL/min/1.73 m2). Secondary endpoints were the development of hypomagnesemia or extrarenal disorders including hyperuricemia and hyperglycemia.ResultsProgression towards CKD-stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (HR 0.29, 95%CI: 0.19-0.44, p < 0.001). Progression towards CKD-stage 3 was also significantly delayed when HNF1B variants involved the HNF1B POUh DNA-binding and transactivation domains rather than the 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 associated positively with hypomagnesemia and negatively with hyperuricemia, but not with hyperglycemia.ConclusionPatients 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 counselling.