TY - JOUR
T1 - Renal and Extrarenal Phenotypes in Patients With HNF1B Variants and Chromosome 17q12 Microdeletions
AU - Buffin-Meyer, Bénédicte
AU - Richard, Juliette
AU - Guigonis, Vincent
AU - Weber, Stefanie
AU - König, Jens
AU - Heidet, Laurence
AU - Moussaoui, Nabila
AU - Vu, Jeanne Pierrette
AU - Faguer, Stanislas
AU - Casemayou, Audrey
AU - Prakash, Richa
AU - Baudouin, Véronique
AU - Hogan, Julien
AU - Alexandrou, Demi
AU - Bockenhauer, Detlef
AU - Bacchetta, Justine
AU - Ranchin, Bruno
AU - Pruhova, Stepanka
AU - Zieg, Jakub
AU - Lahoche, Annie
AU - Okorn, Christine
AU - Antal-Kónya, Violetta
AU - Morin, Denis
AU - Becherucci, Francesca
AU - Habbig, Sandra
AU - Liebau, Max C.
AU - Mauras, Mathilde
AU - Nijenhuis, Tom
AU - Llanas, Brigitte
AU - Mekahli, Djalila
AU - Thumfart, Julia
AU - Tönshoff, Burkhard
AU - Massella, Laura
AU - Eckart, Philippe
AU - Cloarec, Sylvie
AU - Cruz, Alejandro
AU - Patzer, Ludwig
AU - Roussey, Gwenaelle
AU - Vrillon, Isabelle
AU - Dunand, Olivier
AU - Bessenay, Lucie
AU - Taroni, Francesca
AU - Zaniew, Marcin
AU - Louillet, Ferielle
AU - Bergmann, Carsten
AU - Schaefer, Franz
AU - van Eerde, Albertien M.
AU - Schanstra, Joost P.
AU - Decramer, Stéphane
AU - Ariceta, Gema
N1 - Publisher Copyright:
© 2024 International Society of Nephrology
PY - 2024/8
Y1 - 2024/8
N2 - 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.
AB - 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.
KW - chronic kidney disease
KW - genotype-phenotype correlation
KW - HNF1B disease
KW - outcome
UR - http://www.scopus.com/inward/record.url?scp=85194940078&partnerID=8YFLogxK
U2 - 10.1016/j.ekir.2024.05.007
DO - 10.1016/j.ekir.2024.05.007
M3 - Article
AN - SCOPUS:85194940078
SN - 2468-0249
VL - 9
SP - 2514
EP - 2526
JO - Kidney International Reports
JF - Kidney International Reports
IS - 8
ER -