Multicenter Indian registry maps genetic variants and clinical phenotypes in pediatric distal renal tubular acidosis
Investigators analyzed clinical and next-generation sequencing data from 91 children diagnosed with distal renal tubular acidosis across a multicenter Indian registry. Pathogenic or likely pathogenic variants were identified in 61.5% of cases, with SLC4A1 accounting for 51.7% of mutations and twelve novel variants reported. Genotype-phenotype correlations revealed that ATP6V1B1 and ATP6V0A4 variants were linked to earlier presentation and sensorineural hearing loss, while SLC4A1 and WDR72 variants were associated with delayed diagnosis and stunting in 75.8% of patients. The findings underscore a distinct genetic architecture compared to Western cohorts and highlight the diagnostic value of comprehensive molecular testing in guiding clinical management and genetic counseling for rare tubular disorders in South Asian populations.
The original study
Clinical and genetic spectrum of distal renal tubular acidosis in children: findings from Indian tubular disorders registry.
- Authors
- Bhatt GC, Krishnamurthy S, Sinha A, Mittal A, Kumar M, Vijay N, et al.
- Journal
- Pediatric nephrology (Berlin, Germany)
- Type
- Journal Article
- PMID
- 42622870
Original abstract
INTRODUCTION: Distal renal tubular acidosis (dRTA) is a heterogeneous group of disorders of impaired distal acid secretion, leading to normal anion gap metabolic acidosis, growth failure and nephrocalcinosis. Although a genetic basis is well established, the genetic aetiology may differ in Asian populations; however, large multicenter studies from Asia are limited. METHODS: This multicenter observational study, conducted under Indian Council of Medical Research Task Force on Rare Diseases, included incident and prevalent cases of dRTA between 2020 and 2024. Detailed clinical, biochemical, genetic, and outcome data were analysed. RESULTS: Of 96 children initially suspected to have dRTA, five were reclassified following next-generation sequencing. The remaining 91 cases were diagnosed as dRTA. Genetic testing identified pathogenic/likely pathogenic variants in 56 (61.5%), comprising SLC4A1 (51.7%), ATP6V1B1 (21.4%), ATP6V0A4 (14.2%), and WDR72 (12.5%), with 12 novel variants. Children with ATP6V1B1 and ATP6V0A4 variants presented earlier, whereas SLC4A1 and WDR72 variants showed delayed diagnosis despite early symptom onset. Stunting was present in 75.8% of the cohort (median height SDS - 3.6), irrespective of genotype. Nephrocalcinosis (74.7%) and hypokalemia (73.6%) were frequent, which did not differ significantly across genotype. Sensorineural hearing loss was strongly associated with ATP6V1B1 variants (53.8%), while skeletal deformities and rickets predominated in SLC4A1. Chronic kidney disease (CKD) progression occurred in 16.5%, mostly CKD stage 2 or greater; however, none of them progressed to stage 5 CKD. Among SLC4A1 variants, c.2573C > A (p.Ala858Asp) in exon 19 was frequent, accounting for 79.3% (23/29) of variants. CONCLUSIONS: In this large multicentric cohort, the genetic variant spectrum differed from Western populations, with SLC4A1-dRTA being the dominant variety. Stunting was a predominant clinical feature in our cohort, affecting nearly three-quarters of the participants.