GENETIC VARIATIONS AND OUTCOMES IN CHILDREN WITH RENAL TUBULAR DISORDERS: INSIGHTS FROM INDIAN TUBULOPATHY REGISTRY

Introduction:

Renal tubular disorders are a group of rare diseases characterized by phenotypic and genotypic heterogeneity. Affected children may have multisystem involvement and life-threatening complications with adverse impact on quality of life of the patients and family members. The low prevalence, phenotyping variability and paucity of clinical and biological data further restrain our knowledge of renal tubular disorders and their impact on health. The genotype-phenotype correlation of monogenic renal tubular disorders is inadequately studied across populations due to low prevalence and inadequate resources. The objectives of the registry were:

1)  To create a national registry of anonymized clinical data of children with tubular disorders from Pediatric Nephrology centers across India;  2) To screen for variations in a set of genes implicated in the etiology of tubular disorders by whole exome sequencing, using next gen approach; 3)  To track medium term outcomes (renal dysfunction, growth retardation, nephrocalcinosis, hearing loss) of children enrolled in registry  

Methods:

An online registry portal system was developed for data entry from participating centers with following inclusion and exclusion criterion:

 Inclusion criterion i. All children between 1-18 with a clinical diagnosis of renal tubulopathy ii. Parents and extended family members of children who have been diagnosed clinically with renal tubulopathy Exclusion criterion i. Those refusing consent were excluded ii. Individual with an identifiable, non-genetic etiology for the renal tubular disorder, such as a specific nephrotoxic antibiotic or native medication exposure, mitochondrial disorder, or infection such as pyelonephritis were excluded The registry included both incident and prevalent cases of tubulopathy. For enrolment in registry considered rates of various prognostic outcomes like CKD, growth failure, nephrocalcinosis and hearing loss.

Molecular Methods Samples obtained from the patients, parents and other relatives, where relevant, were used to extract DNA. The DNA will be stored in a bio-repository. The high-quality DNA was used to prepare paired-end libraries that was sequenced using the Illumina platform. The sequencing data obtained was mapped to the reference genome to identifythe SNP (Single Nucleotide Polymorphism) and other CNV (Copy Number Variation). Best practices suggested by GATK guidelines for identification of variants were followed to minimize the chances of erroneous variant calling. Only high-quality variants obtainedafter filtering low scoring variant calls were used for downstream analysis. 

Results:

Two hundred thirty-three patients with renal tubular disorders had been registered till June 2024.Most of the patients enrolled in the registry had distal RTA, followed by Bartter and Gitelman syndrome and proximal RTA. Figure 1 shows the pie chart of clinical presentation at the time of recruitment.

Results of genotype: Genetic testing was available from 158 participants.  The mean age of the patients was 8.73 (5.9) years. Of patients with dRTA in whom NGS report is available, the diagnosis 48 patients were confirmed through genetic testing (diagnostic yield: 63%) . Seggregation analysis was done in 51 cases.Table 1 shows the details of variant classification as per American college of Medical genetics and Genomics (ACMG) criterion. Pathogenic/ likely pathogenic variants included SLC4A1(23), ATP6VOA4(7), ATP6VIB1 (9), WDR72 ((8) in children with distal renal tubular disorders.The common variants reported in children with proximal tubular disorder were: CTNS (9); OCRL (3); FAH(1); variants reported in Barrter Gitelman syndrome were: CLCNKB (6); SLC12A3(4); KCNJ1(3).

Conclusions:

The present registry is  large-scale study of a Indian  tubular disorder  cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of tubular disorders in india

I have potential conflict of interest to disclose.
The research is funded by Indian Council of Medical Research (ICMR) task force on rare disease no 33/12/2019-RF/Rare/BMS

I did not use generative AI and AI-assisted technologies in the writing process.