BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.
BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.
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Authors: Moumita Chaki; Julia Hoefele; Susan J Allen; Gokul Ramaswami; Sabine Janssen; Carsten Bergmann; John R Heckenlively; Edgar A Otto; Friedhelm Hildebrandt Journal: Kidney Int Date: 2011-08-24 Impact factor: 10.612
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Authors: Weibin Zhou; Edgar A Otto; Andrew Cluckey; Rannar Airik; Toby W Hurd; Moumita Chaki; Katrina Diaz; Francis P Lach; Geoffrey R Bennett; Heon Yung Gee; Amiya K Ghosh; Sivakumar Natarajan; Supawat Thongthip; Uma Veturi; Susan J Allen; Sabine Janssen; Gokul Ramaswami; Joanne Dixon; Felix Burkhalter; Martin Spoendlin; Holger Moch; Michael J Mihatsch; Jerome Verine; Richard Reade; Hany Soliman; Michel Godin; Denes Kiss; Guido Monga; Gianna Mazzucco; Kerstin Amann; Ferruh Artunc; Ronald C Newland; Thorsten Wiech; Stefan Zschiedrich; Tobias B Huber; Andreas Friedl; Gisela G Slaats; Jaap A Joles; Roel Goldschmeding; Joseph Washburn; Rachel H Giles; Shawn Levy; Agata Smogorzewska; Friedhelm Hildebrandt Journal: Nat Genet Date: 2012-07-08 Impact factor: 38.330
Authors: Sylvia Hoff; Jan Halbritter; Daniel Epting; Valeska Frank; Thanh-Minh T Nguyen; Jeroen van Reeuwijk; Christopher Boehlke; Christoph Schell; Takayuki Yasunaga; Martin Helmstädter; Miriam Mergen; Emilie Filhol; Karsten Boldt; Nicola Horn; Marius Ueffing; Edgar A Otto; Tobias Eisenberger; Mariet W Elting; Joanna A E van Wijk; Detlef Bockenhauer; Neil J Sebire; Søren Rittig; Mogens Vyberg; Troels Ring; Martin Pohl; Lars Pape; Thomas J Neuhaus; Neveen A Soliman Elshakhs; Sarah J Koon; Peter C Harris; Florian Grahammer; Tobias B Huber; E Wolfgang Kuehn; Albrecht Kramer-Zucker; Hanno J Bolz; Ronald Roepman; Sophie Saunier; Gerd Walz; Friedhelm Hildebrandt; Carsten Bergmann; Soeren S Lienkamp Journal: Nat Genet Date: 2013-06-23 Impact factor: 38.330