| Objective: Primary distal renal tubular acidosis(d RTA)is a rare inherited kidney disease that is characterized by a failure of acid secretion by the alpha-intercalated cells of the cortical and outer medullary collecting ducts of the distal nephron,resulting in persistent metabolic acidosis with a normal anion gap.The aim of this study was to analyze the variants of 65 Chinese patients with primary d RTA and explore the correlation between their genotype and phenotype.Methods: In this study,we collected data on patients with primary d RTA who were diagnosed or treated in the affiliated Hospital of Qingdao University and the affiliated Qingdao Municipal Hospital of Qingdao University from April 2010 to December 2022.Trio wholeexome sequencing or Sanger sequencing validation was used to analyze gene variants.The pathogenicity of variants was evaluated according to the 2015 American College of Medical Genetics and Genomics Standards and Guidelines(ACMG),and the characteristics of variants in each gene were then summarized.A minigene assay was used to analyzed the probable splicing variants impacting the intron-exon junction site.According to the different involved genes and modes of inheritance,the patients were divided into five groups: SLC4A1 autosomal dominant inheritance(AD)group,SLC4A1 autosomal recessive inheritance(AR)group,ATP6V0A4 group,ATP6V1B1 group,and Negative group.To characterize the clinical manifestations of these groups,clinical and biochemical data from these patients were gathered and retrospectively evaluated.The differences among the various groups were statistically evaluated.The majority of patients were treated with an oral citrate mixture.To assess the efficacy of the medications,the patient’s height,weight,blood gas analysis,blood and urine biochemical parameters,and kidney ultrasound were all checked on a regular schedule.Results: 1.9 variants of SLC4A1 gene,21 variants of ATP6V0A4 gene,and 18 variants of ATP6V1B1 gene have been identified in 65 patients with d RTA,and of which 17 were novel ones.2.By a minigene splicing assay,six variants(c.2257+1G>A,c.2258-?1G>C and c.639+1G>A in ATP6V0A4 gene;c.687G>A,c.785+1G>A and c.786-1G>C in ATP6V1B1gene)identified in this study have been revealed to be splicing mutations and affected normal pre-m RNA splicing.3.16 patients with autosomal dominant d RTA,as well as 4 patients with autosomal recessive d RTA coexisting with ovoid erythrocytosis,were caused by genetic defects in SLC4A1;20 and 12 patients with recessive d RTA were resulted by genetic defects in ATP6V0A4 and ATP6V1B1 respectively;2 children with d RTA were found to carry monoallelic defects in ATP6V1B1;no causal gene was identified in 11 patients.Of the 65 patients,9(14%)were homozygotes,18(28%)were heterozygotes,and 27(42%)were compound heterozygotes.4.One patient presented with an incomplete d RTA,whereas the other 64 patients had complete d RTA.The frequency of CKD in adults,children and infants was 100%,25% and4%,separately.5.One patient(5%)harboring SLC4A1 mutations showed mild sensorineural hearing loss(SNHL);five(36%)carrying ATP6V1B1 variants were revealed with extreme SNHL,three patient(21%)with moderate-to-severe SNHL;three(15%)with ATP6V0A4 variants were demonstrated with moderate SNHL;and one patient(9%)with unknown mutation showed mild SNHL.6.By the treatment based on potassium citrate and sodium citrate,the growth impairment and electrolyte disturbance of the majority of patients has been significantly improved,one child died of severe pneumonia at the age of 7-month-old.Conclusion: In our study,48 variants of SLC4A1,ATP6V0A4 & ATP6V1B1 genes in 65 Chinese patients with d RTA has been identified in present study,including 17 novel ones.This study is the largest cohort investigation of primary d RTA in China and revealed the genotype and phenotype of d RTA in Chinese populations,which can be used as a useful reference for further clinical research and genetic counseling. |
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