Background 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.
Methods 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.
Results 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).
Conclusions 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.
- child health
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XT, CL and XL contributed equally.
Contributors XT, CL and XL contributed equally to this work. JR, QS and HX are co-corresponding authors. HX, CL and XL conceived and designed the study. JC, XF, JL, GC, ZC, YZ, LC, LH, SZ, BZ, SJ and XG collected the blood sample and clinical data. DM, YW, DX and XJ performed gene sequencing. YL, JR, AZ and ZR analysed clinical data. XT and QS wrote the manuscript. All authors reviewed and approved the manuscript.
Funding This work was supported by grant NSFC-81801545 from National Natural Science Foundation of China (XT); grant 2017ZZ01008 from Shanghai Municipal Health Commission (HX), grant 2018YFA0801102 from National Key Research and Development Project, grant NSFC-8182207 from National Natural Science Foundation of China (JR), grant 19XD1420600 from Program of Shanghai Academic/Technology Research Leader (JR), and grant 2019-RC-HL_020 from Chinese Academy of Medical Sciences (JR) and grant LHGJ20190923 from Henan Municipal Health Commission.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The Institutional Review Board of the Children’s Hospital of Fudan University approved and monitored this study involving the 10 participating centres. All participants provided written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.
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