Genetic Testing,Treatment And Prognosis In Han Ethnic Children With Steroid-Resistant Nephrotic Syndrome With Mutations In ADCK4

Objective Steroid-resistant nephrotic syndrome(SRNS)indicates an unfavorable prognosis.If remission is not achieved,there is a 50 % risk of progression to end-stage renal disease(ESRD)within 5 years of diagnosis.The transcript of ADCK4 gene encodes a protein of the CoQ10 biosynthetic pathway,which localizes to the mitochondria and foot processes in podocytes.Mutations in ADCK4 cause inherited structural defects in glomerular filtration barrier,identified as a mechanism of SRNS.In foreign countries,it has respectively reported that 41 patients with SRNS were caused by mutations in ADCK4.In China,1 patient with ADCK4 mutations was reported.The patients with SRNS caused by ADCK4 mutations have partial remission following CoQ10 treatment at the early stage.Progressing to ESRD,the patients have to be treated with hemodialysis or renal transplant.However,there were few reports on the genetic testing and treatment in Han Ethnic children with SRNS caused by ADCK4 mutations.The prognosis of renal transplant in patient with SRNS caused by ADCK4 mutations has also been unknown.Therefore,our objectives were to investigate the characteristic of ADCK4 mutations in Han Ethnic Children with SRNS,the treatment and prognosis of children with SRNS caused by ADCK4 mutations.Methods Genomic DNA was extracted from the peripheral blood leukocytes of the 11 patients with SRNS and 1 patient with heavy proteinuria.We performed genetic testing of every exon of the ADCK4 gene inclusive 25 bases from 3' end and 25 bases from 5' end in the 12 patients using targeted sequencing and next generation sequencing.We focused on non-synonymous variants,nonsense variants,inserted or deleted mutations and an MAF value of < 1% or unknown in the 1000 Genomes Project.These mutations were confirmed by Sanger sequencing.Furthermore,we investigated whether the mutations were a potential disease-causing mutation according different scoring systems.The patients diagnosed with ADCK4 mutations were treated with COQ10,hemodialysis or renal transplant and were observed the prognosis.Results The compound heterozygous mutations in the ADCK4 gene were detected in 4 of 12 patients.Four mutations in ADCK4 were identified in the 4 patients.Mutation in ADCK4,ADCK4 532C>T,was reported to be pathogenic.Mutations in ADCK4,ADCK4 448C>T,ADCK4 748 G>C and ADCK4 1468C>T,were novel.According to the bioinformatics analysis,all 3 novel mutations were pathogenic.The 4 patients were definitely diagnosed with ADCK4-associated glomerulopathy.The 1 patient was treated with CoQ10 for 5 months.At the last follow-up visit,the proteinuria decreased from 3+ to 1+,and urea was 16.0 mmol/L,and creatinine 248.7?mol/L.The one patient progressed to ESRD and remind under treatment with hemodialysis for renal transplant in stable condition.The other two patients received successful cadaveric renal transplant after progressing to ESRD.There was not any clinical and laboratory evidence of recurrent has been found over 10 years.At the last follow-up visit,proteinuria was negative in two patients,and urea was 5.5 mmol/L,7.9 mmol/L,and creatinine was 81?mol/L,114?mol/L in two patients,respectively.Conclusions ADCK4 mutations were identified in 33.3%(4/12)of Han Ethnic children with SRNS or heavy proteinuria.ADCK4-associated glomerulopathy can achieve improvement with CoQ10 treatment at the early stage.After progressing to ESRD,renal transplantation has a better long term prognosis in the patients caused by ADCK4 mutations.These results suggest that it should be necessary to perform genetic testing of ADCK4 in Han Ethnic children with SRNS or heavy proteinuria,which will contribute to guiding treatment and evaluating the prognosis.