Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies.

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.

[1]  Daniel Bell,et al.  Ciliopathies , 2018, Radiopaedia.org.

[2]  N. Cengiz,et al.  Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis. , 2017, American journal of human genetics.

[3]  N. Cengiz,et al.  Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis. , 2017, American journal of human genetics.

[4]  H. Omran,et al.  Nephronophthisis and Autosomal Dominant Interstitial Kidney Disease (ADIKD) , 2016 .

[5]  H. Bolz,et al.  The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy , 2015, British Journal of Ophthalmology.

[6]  M. Wolf,et al.  Nephronophthisis and related syndromes , 2015, Current opinion in pediatrics.

[7]  W. van Biesen,et al.  Providing guidance in the dark: rare renal diseases and the challenge to improve the quality of evidence. , 2014, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[8]  R. Roepman,et al.  ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3 , 2013, Nature Genetics.

[9]  F. Hildebrandt,et al.  Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy , 2013, Human Genetics.

[10]  Sophie,et al.  ANKS 6 is a central component of a nephronophthisis module linking NEK 8 to INVS and NPHP 3 , 2013 .

[11]  H. Omran,et al.  High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing , 2012, Journal of Medical Genetics.

[12]  F. Hildebrandt,et al.  Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience. , 2012, Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia.

[13]  H. Moch,et al.  FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair , 2012, Nature Genetics.

[14]  A. Munnich,et al.  Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. , 2012, American journal of human genetics.

[15]  B. Schermer,et al.  Clinical spectrum and pathogenesis of nephronophthisis , 2012, Current opinion in nephrology and hypertension.

[16]  J. Heckenlively,et al.  Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. , 2011, Kidney international.

[17]  J. Sayer,et al.  Nephronophthisis: A Genetically Diverse Ciliopathy , 2011, International journal of nephrology.

[18]  V. Sheffield,et al.  Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome. , 2011, Archives of ophthalmology.

[19]  F. Coppieters,et al.  CEP290, a gene with many faces: mutation overview and presentation of CEP290base , 2010, Human mutation.

[20]  K. Tory,et al.  Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11) , 2009, Journal of Medical Genetics.

[21]  H. Cross,et al.  Lethal cystic kidney disease in Amish neonates associated with homozygous nonsense mutation of NPHP3. , 2009, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[22]  K. Tory,et al.  Mutations of NPHP2 and NPHP3 in infantile nephronophthisis. , 2009, Kidney international.

[23]  M. Siimes,et al.  Mechanism underlying early anaemia in children with familial juvenile nephronophthisis , 1996, Pediatric Nephrology.

[24]  F. Hildebrandt,et al.  Nephronophthisis: disease mechanisms of a ciliopathy. , 2009, Journal of the American Society of Nephrology : JASN.

[25]  Sophie Saunier,et al.  Nephronophthisis , 2008, Pediatric Nephrology.

[26]  R. Lewis,et al.  Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome , 2008, Nature Genetics.

[27]  H. Omran,et al.  When cilia go bad: cilia defects and ciliopathies , 2008, Nature Reviews Molecular Cell Biology.

[28]  H. Omran,et al.  When cilia go bad: cilia defects and ciliopathies , 2007, Nature Reviews Molecular Cell Biology.

[29]  F. Hildebrandt,et al.  Nephronophthisis-associated ciliopathies. , 2007, Journal of the American Society of Nephrology : JASN.

[30]  E. Bertini,et al.  Nephronophthisis type 1 deletion syndrome with neurological symptoms: prevalence and significance of the association. , 2006, Kidney international.

[31]  Madeline A. Lancaster,et al.  Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome , 2006, Nature Genetics.

[32]  R. Reinhardt,et al.  Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin , 2005, Nature Genetics.

[33]  I. Glass,et al.  The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. , 2004, American journal of human genetics.

[34]  D. Geary,et al.  Ultrasound findings in juvenile nephronophthisis , 1996, Pediatric Nephrology.

[35]  Bernhard Schermer,et al.  Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis , 2003, Nature Genetics.

[36]  J. Weissenbach,et al.  Characterization of the NPHP1 locus: mutational mechanism involved in deletions in familial juvenile nephronophthisis. , 2000, American journal of human genetics.

[37]  F Hildebrandt,et al.  Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. , 2000, American journal of human genetics.

[38]  G. Ghiggeri,et al.  Nephronophthisis-medullary cystic disease: clinical and genetic aspects. , 1998, Journal of nephrology.

[39]  W. Shingleton,et al.  Electrovaporization of the Prostate versus Laser Ablation of the Prostate in Men with Benign Prostatic Hypertrophy:A Pressure-Flow Analysis , 1998, Urologia Internationalis.

[40]  F. Hildebrandt,et al.  A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1 , 1997, Nature Genetics.

[41]  N. Gretz,et al.  Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie. , 1997, Kidney international.

[42]  D. Le Paslier,et al.  Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. , 1996, Human molecular genetics.

[43]  J. Beckmann,et al.  A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p , 1993, Nature Genetics.

[44]  K. Schärer,et al.  Children with chronic renal failure in the Federal Republic of Germany: I. Epidemiology, modes of treatment, survival. Arbeits- gemeinschaft für Pädiatrische Nephrologie. , 1985, Clinical nephrology.

[45]  A. Prader,et al.  [Familial, juvenile nephronophthisis (idiopathic parenchymal contracted kidney)]. , 1951, Helvetica paediatrica acta.

[46]  J. Graham,et al.  CONGENITAL MEDULLARY CYSTS OF THE KIDNEYS WITH SEVERE REFRACTORY ANEMIA , 1945 .