Buffin-Meyer Bénédicte, Richard Juliette, Guigonis Vincent, Weber Stefanie, König Jens, Heidet Laurence, Moussaoui Nabila, Vu Jeanne-Pierrette, Faguer Stanislas, Casemayou Audrey, Prakash Richa, Baudouin Véronique, Hogan Julien, Alexandrou Demi, Bockenhauer Detlef, Bacchetta Justine, Ranchin Bruno, Pruhova Stepanka, Zieg Jakub, Lahoche Annie, Okorn Christine, Antal-Kónya Violetta, Morin Denis, Becherucci Francesca, Habbig Sandra, Liebau Max C, Mauras Mathilde, Nijenhuis Tom, Llanas Brigitte, Mekahli Djalila, Thumfart Julia, Tönshoff Burkhard, Massella Laura, Eckart Philippe, Cloarec Sylvie, Cruz Alejandro, Patzer Ludwig, Roussey Gwenaelle, Vrillon Isabelle, Dunand Olivier, Bessenay Lucie, Taroni Francesca, Zaniew Marcin, Louillet Ferielle, Bergmann Carsten, Schaefer Franz, van Eerde Albertien M, Schanstra Joost P, Decramer Stéphane
National Institute of Health and Medical Research (INSERM), UMR 1297, Institute of Cardiovascular and Metabolic Disease, Toulouse, France.
University Paul Sabatier, Toulouse-III, Toulouse, France.
Kidney Int Rep. 2024 May 16;9(8):2514-2526. doi: 10.1016/j.ekir.2024.05.007. eCollection 2024 Aug.
Hepatocyte nuclear factor 1-beta () 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 variants were associated with kidney survival in a large patient population with disease.
This was a retrospective observational study involving 521 patients with disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the genotype ( 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 m). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia.
Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19-0.44, < 0.001). Progression toward CKD stage 3 was also significantly delayed when variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POU) DNA-binding and transactivation domains rather than the POU-specific domain (POU) DNA-binding domain (HR: 0.15 [95% CI: 0.06-0.37), < 0.001 and HR: 0.25 (95% CI: 0.11-0.57), = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia.
Patients with the 17q12del display a significantly better kidney survival than patients with other variants; and for the latter, variants in the POU DNA-binding domain lead to the poorest kidney survival. These are clinically relevant kidney genotype-phenotype correlations that inform genetic counseling.
肝细胞核因子1β（HNF1β）基因变异或17号染色体q12缺失（17q12del）是发育性肾病最常见的单基因病因。虽然神经发育障碍与17q12del有关，但关于肾功能演变的特定基因型-表型关联尚未完全明确。在此，我们旨在确定17q12del或特定HNF1β变异是否与一大群患有该疾病的患者的肾脏存活情况相关。
这是一项回顾性观察性研究，纳入了来自14个国家的521例患有该疾病的患者，这些患者使用了欧洲罕见肾病参考网络，拥有关于HNF1β基因型（HNF1β变异或17q12del）的详细信息。中位随访时间为11年，每位患者进行6次随访。主要终点是进展至慢性肾脏病（CKD）3期（估计肾小球滤过率[eGFR]<60 ml/min/1.73 m²）。次要终点是低镁血症或肾外疾病的发生，包括高尿酸血症和高血糖症。
与携带HNF1β变异的患者相比，携带17q12del的患者进展至CKD 3期明显延迟（风险比[HR]：0.29，95%置信区间[CI]：0.19 - 0.44，P<0.001）。当HNF1β变异涉及HNF1B Pit-1、Oct-1和Unc-86同源结构域（POU）DNA结合和反式激活结构域而非POU特异性结构域（POU）DNA结合结构域时，进展至CKD 3期也明显延迟（HR分别为0.
