Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy.

Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children. Exploring the correlation between the phenotype and genotype of NPHP-RC is helpful for early diagnosis and management. We investigated the phenotype and genotype spectra of NPHP-RC in a Chinese multicentre cohort. Crosss-ectional and longitudinal data of 60 patients from 57 families with pathogenic NPHP-RC gene mutations distributed in 22 regions of China were collected into a unified, anonymous database. The mean observation time of this cohort was 3.5±3.1 years. Mutations in NPHP1 and NPHP3 were the most common genetic defects. Overall, 45% of patients presented with isolated nephronophthisis (NPH), and 55% exhibited the extrarenal phenotype, which frequently involved the liver (41.7%, n=25), central nervous system (26.7%, n=16), eyes (26.7%, n=16) and skeletal system (11.7%, n=7). Accidental detection of elevated serum creatinine and non-specific symptoms caused by chronic kidney disease occurred in 65% of patients. Patients carrying NPHP1 mutations mainly presented with isolated NPH (90%, 18/20) and progressed to ESRD at a mean age of 12.9±0.5 years. The mean age of ESRD onset in the non-NPHP1 group was lower than that in the NPHP1 group (6.2±1.4 years, p<0.001), especially for patients carrying NPHP3 mutations (3.1±1.2 years), showing a heterogeneous phenotype characterised by Bardet-Biedl syndrome (12.5%, n=5), Joubert syndrome (7.5%, n=3), COACH syndrome (2.5%, n=1), Mainzer-Saldino syndrome (2.5%, n=1), short-rib thoracic dysplasia (2.5%, n=1) and unclassified symptoms (32.5%, n=13). The Chinese Children Genetic Kidney Disease Database registry characterised the spectrum of the phenotype and genotype of NPHP-RC in the Chinese population. NPHP1 and NPHP3 were the most common pathogenic genes. Rapid progression to ESRD and liver involvement were noted in patients with NPHP3 mutations.

Tang X ，Liu C ，Liu X ，Chen J ，Fan X ，Liu J ，Ma D ，Cao G ，Chen Z ，Xu D ，Zhu Y ，Jiang X ，Cheng L ，Wu Y ，Hou L ，Li Y ，Shao X ，Zheng S ，Zhang A ，Zheng B ，Jian S ，Rong Z ，Su Q ，Gao X ，Rao J ，Shen Q ，Xu H ，Chinese Children Genetic Kidney Disease Database (CCGKDD) ，“Internet Plus” Nephrology Alliance of the National Center for Children’s Care ... -  《-》

Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies.

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. 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. 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. Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.

König J ，Kranz B ，König S ，Schlingmann KP ，Titieni A ，Tönshoff B ，Habbig S ，Pape L ，Häffner K ，Hansen M ，Büscher A ，Bald M ，Billing H ，Schild R ，Walden U ，Hampel T ，Staude H ，Riedl M ，Gretz N ，Lablans M ，Bergmann C ，Hildebrandt F ，Omran H ，Konrad M ，Gesellschaft für Pädiatrische Nephrologie (GPN) ... -  《-》

Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP.

Nephronophthisis-related ciliopathies (NPHP-RC) have strong genotype and phenotype heterogeneity, and the transplantation strategy of Boichis syndrome is still controversial. Our purpose was to examine associations of genotype and phenotype in children with NPHP-RC and analyze the transplantation strategies of different phenotypes. The records of children with NPHP treated at our center from 01/2018 to 03/2021 were retrospectively reviewed. Inclusion criteria were a diagnosis of NPHP, received kidney transplantation, and received whole exome sequencing (WES) or nephropathy gene panel testing. Twenty-nine children with NPHP were included. Nine children (31%) had NPHP1 mutations, and all presented with isolated nephropathy. Eighteen of 20 patients with non-NPHP1 mutations had compound heterozygous mutations, and 70% had extrarenal phenotype. Age at disease presentation (11.2 ± 1.94 years) and the development of kidney failure (12.4 ± 2.70 years) were later in children with NPHP1 mutations than those with non-NPHP1 mutations (5.2 ± 2.83 years and 5.7 ± 2.92 years, respectively). Four of six children with NPHP3 mutations were diagnosed with Boichis syndrome due to liver fibrosis. Isolated kidney transplantation resulted in good outcomes for patients with mild or moderate liver fibrosis without portal hypertension, while cholestasis was common postoperatively and could be resolved with ursodeoxycholic acid. NPHP1 mutations are the most common in children with NPHP, and the phenotype of NPHP1 mutation is significantly different from that of non-NPHP1 mutation. For NPHP patients with mild to moderate liver fibrosis without portal hypertension, timely treatment of cholestasis could prevent the rapid progression of liver function damage after isolated kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Li J ，Su X ，Zhang H ，Wu W ，Li J ，Chen Y ，Li J ，Fu Q ，Wu C ，Zhong X ，Wang C ，Liu L ... -  《-》

Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience.

Soliman NA ，Hildebrandt F ，Otto EA ，Nabhan MM ，Allen SJ ，Badr AM ，Sheba M ，Fadda S ，Gawdat G ，El-Kiky H ... -  《-》

Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies.

Chaki M ，Hoefele J ，Allen SJ ，Ramaswami G ，Janssen S ，Bergmann C ，Heckenlively JR ，Otto EA ，Hildebrandt F ... -  《-》