Genetic Background And Clinical Study Of Children With Congenital Renal Tubular Acidosis

BackgroundThe primary distal renal tubular acidosis is most common in children with congenital renal tubular acidosis.Primary distal renal tubular acidosis(dRTA)is caused by genetic defects that result in uric acid dysfunction in the presence of hyperchloremic metabolic acidosis.The main clinical features of dRTA are polydipsia,loss of appetite,vomiting,diarrhea and/or constipation,and polyuria.Chronic acidosis and secondary alterations such as polyuria,polydipsia,and vomiting affect growth,leading to failure to thrive.In general,dRTA may have a better prognosis if diagnosed early and subjected continued alkaline treatment.Untreated,dRTA causes rickets and/or growth retardation in children and osteomalacia in adults and gradual deterioration of renal function with time.Primary distal RTA can be transmitted as either an autosomal dominant or an autosomal recessive trait.The autosomal dominant phenotype typically appears in a mild form in adolescence.The autosomal recessive phenotype usually result in growth retardation,and may or not lead to deafness.The parents of children with this variant are unaffected.Autosomal recessive dRTA is associated with mutations in solute carrier family 4 member 1(SLC4A1),ATPase H+ transporting VO subnit A4(ATP6V0A4),and ATPase H+ transporting V1 subunit B1(ATP6V1B1).However,in approximately 20%of patients with dRTA,no mutations were found in these genes,suggesting that defects in other transporters or channels might also be involved in dRTA pathogenesis.Next generation sequencing(NGS)provides coverage of more than 95%of the exons that contain 85%of the disease-causing mutations in Mendelian disorders.Whole-exome sequencing is useful to recognize new pathogenic genes and in evaluating the pathogenesis of a disease.Objective:The aim of the present study was to demonstrate the genetic diagnosis of 16 Chinese children with distal renal tubular acidosis by whole-exome sequencing.Methods:From Jan 2010 to Sept 2015,33 RTA children were hospital in the Children's Hospital of Zhejiang University School of Medicine.To study clinical and biochemical features of 33 RTA children.16 unrelated patients with distal renal tubular acidosis were recruited to the present study to investigate the possibility of genetic diagnosis and the relationship between phenotype and genotype in these patients.The whole-exome sequencing technique was applied to the 16 patients with primary distal renal tubular acidosis.Sanger sequencing was used to confirm mutation identified by whole-exome sequencing.Results:Clinical and biological features in these children with primary renal tubular acidosis included hyperchloremic metabolic acidosis,impaired growth,hypokalemia,nephrocalcinosis,nephrolithiasis,hypercalciuria,hypocitraturia,and rickets or osteomalacia.Seventeen mutations of the solute carrier family 4 member 1(SLC4A1),ATPase H+ transporting VO subunit A4(ATP6V0A4),ATPase H+ transporting V1 subunit B1(ATP6V1B1),WNK lysine deficient protein kinase 1(WNK1)and the claudin 16(CLDN16)were identified in 15 of the children with dRTA,and 14 of these mutations are novel.Only 1 patient was negative for any mutations in the screening.Conclusion:Our results demonstrated the existence of the SLC4A1,ATP6V1B1,ATP6V0A4,WNK1 and CLDN16 mutations in Chinese children with distal renal tubular acidosis and disclosed that compound heterozygosity at two or more different but related genes can be responsible for the pathogenesis of distal renal tubular acidosis.This study also indicates that whole-exome sequencing technique is a labor and cost effective means of analyzing associated genes of children congenital renal tubular acidosis.