Introduction: Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder characterized by an impaired urinary acidification process in distal nephrons that results in the production of alkaline urine. Loss of function variants in any of the three genes, ATP6V0A4, ATP6V1B1, or SLC4A1, which all play a role in normal acidification of urine by kidneys, may lead to dRTA. Objective: This study was designed to identify genetic variants underlying dRTA in Pakistani patients using whole exome sequencing, followed by confirmatory Sanger sequencing. Materials and Methods: Patients were identified following presentation with characteristic clinical features of dRTA including vomiting, dehydration, and highly alkaline urine with metabolic acidosis during the first few days of life. Whole exome sequencing and Sanger sequencing were employed for genetic analyses of the patients. In silico analyses of the identified variants were performed using web-based bioinfomatics programs. Results: Through whole exome sequencing, we identified two splice site variants (c.2257 + 1G>A and c.722 + 5G>A) in the ATP6V0A4 gene that likely underly the disease phenotype in the two families. Multiple in silico tools predicted these variants to affect the respective splice sites supporting their likely role in pathogenesis. Conclusion: The study extends the spectrum of ATP6V0A4 variants associated with dRTA and should benefit the genetic counseling and prenatal diagnosis of the affected families.

中文翻译：

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使用全外显子组测序对巴基斯坦患者远端肾小管性酸中毒的分子诊断和遗传变异的鉴定。

简介：原发性远端肾小管性酸中毒（dRTA）是一种罕见的遗传疾病，其特征是远端肾单位中尿酸化过程受损，导致碱性尿液的产生。ATP6V0A4，ATP6V1B1或SLC4A1这三个基因中的任何一个均丧失功能变体，这些变体均在肾脏正常尿液酸化中起作用，可能导致dRTA。目的：本研究旨在通过全外显子组测序，然后通过验证性Sanger测序，鉴定巴基斯坦患者dRTA的遗传变异。材料和方法：病人经鉴定后具有dRTA的特征性临床特征，包括生命最初几天的呕吐，脱水和高碱性尿伴代谢性酸中毒。使用全外显子组测序和Sanger测序对患者进行遗传分析。使用基于网络的生物信息学程序对已鉴定的变体进行计算机分析。结果：通过整个外显子组测序，我们在ATP6V0A4基因中鉴定出两个剪接位点变体（c.2257 + 1G> A和c.722 + 5G> A），这可能是两个家族中疾病表型的基础。多种计算机软件工具预测这些变体会影响各自的剪接位点，从而支持其在发病中的可能作用。结论：该研究扩大了与dRTA相关的ATP6V0A4变体的范围，应有利于受影响家庭的遗传咨询和产前诊断。通过整个外显子组测序，我们在ATP6V0A4基因中鉴定了两个剪接位点变体（c.2257 + 1G> A和c.722 + 5G> A），这可能是两个家族中疾病表型的基础。多种计算机软件工具预测这些变体会影响各自的剪接位点，从而支持其在发病中的可能作用。结论：该研究扩大了与dRTA相关的ATP6V0A4变体的范围，应有利于受影响家庭的遗传咨询和产前诊断。通过整个外显子组测序，我们在ATP6V0A4基因中鉴定了两个剪接位点变体（c.2257 + 1G> A和c.722 + 5G> A），这可能是两个家族中疾病表型的基础。多种计算机软件工具预测这些变体会影响各自的剪接位点，从而支持其在发病中的可能作用。结论：该研究扩大了与dRTA相关的ATP6V0A4变体的范围，应有利于受影响家庭的遗传咨询和产前诊断。