Renal hypouricemia
Description
Research Hypothesis: Our hypothesis explores the role of compound heterozygous mutations in the SLC2A9 gene, particularly focusing on the c.1004T>A mutation, in contributing to recurrent episodes of exercise-induced acute kidney injury (EIAKI), even in the absence of high-intensity physical activity. This study aims to enhance the understanding of the genetic basis of Renal Hypouricemia Type 2 (RHUC2) and the mechanisms by which these mutations lead to kidney injury. Data Description and Collection: The data were collected from genetic sequencing and clinical analysis of a 30-year-old male patient who experienced recurrent EIAKI despite engaging only in low-to-moderate intensity physical activity. The key genetic findings include: SLC2A9 (NM_020041.3) c.646G>A p.(Gly216Arg) Location: Chr4:9982251 ClinVar ID: 1049499 (Uncertain significance) SLC2A9 (NM_020041.3) c.1004T>A p.(Ile335Asn) Location: Chr4:9909968 Notable Findings: Variant of Uncertain Significance (VUS): The c.1004T>A (Ile335Asn) mutation in the SLC2A9 gene, though previously reported, is classified as a Variant of Uncertain Significance (VUS). Its association with RHUC2, especially in the context of recurrent EIAKI, underscores the complexity of this condition. Genetic Heterogeneity: These findings reinforce the genetic heterogeneity of RHUC2, highlighting the importance of comprehensive genetic testing for accurate diagnosis in patients with unexplained acute kidney injury, particularly when recurrent episodes follow physical activity.
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Outline for Data Collection and Reproduction:- This outline provides a concise overview of the methodologies used for data collection and analysis in our study of Renal Hypouricemia Type 2 (RHUC2). Clinical Data Collection:- Patient History and Examination: A detailed medical history focused on episodes of acute kidney injury (AKI) related to physical activity. Standard physical exams assessed overall health. Laboratory Tests: Blood and urine samples were analyzed, including serum creatinine, uric acid levels, complete blood count (CBC), liver function tests (LFTs), and urine protein-to-creatinine ratio. Imaging Studies: Ultrasound and CT scans were performed to rule out structural abnormalities. Results were thoroughly documented. Renal Biopsy: Kidney tissue was analyzed using electron microscopy to assess the glomerular basement membrane and other structures. Genetic Analysis:- DNA Extraction: Genomic DNA was extracted using the Qiagen DNeasy Blood & Tissue Kit, with quality assessed by spectrophotometry (NanoDrop) and gel electrophoresis. Whole-Genome Sequencing (WGS): WGS was performed using a high-throughput platform (Illumina HiSeq), including library preparation, sequencing, and data processing. Variant Identification and Annotation: Bioinformatic tools identified and annotated SLC2A9 variants, specifically c.646G>A (p.Gly212Arg) and c.1004T>A (p.Ile335Asn), using GATK for variant calling and ANNOVAR for annotation. Pathogenicity Prediction: Multiple in silico tools (e.g., MutPred, FATHMM, PolyPhen-2) were employed to assess the potential functional impact of the variants on GLUT9 protein. Data Interpretation:- Variant Classification: Variants were classified based on pathogenicity, population frequency (gnomAD), and predicted protein function impact, following ACMG guidelines. Family Testing: Although family testing to confirm the "in trans" configuration was recommended, it was not pursued by the patient's family. Data Documentation and Sharing:- Documentation: All genetic and clinical data were meticulously documented, organized in a structured format for ease of analysis. Sharing: Data was shared with the scientific community via Mendeley Data (Vukkadala, Muralinath; Paladugu, Niranjana Rekha, 2024, “Renal hypouricemia”, Mendeley Data, V1, doi: 10.17632/7z84mkdgn9.1). Reagents and Software Reagents: DNA extraction and sequencing were conducted using Qiagen kits and platform-specific reagents. Software: GATK, ANNOVAR, and in silico tools were used for variant calling, annotation, and pathogenicity prediction. Conclusion:- This detailed yet concise methodology allows for reproducibility and further exploration of RHUC2's genetic underpinnings, aiding in the broader understanding of the disorder and its clinical implications.