Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology.
This was a multicenter descriptive study wherein children (< 18 years) with clinically suspected tubular disorders were recruited for molecular testing through WES. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were done when required. Variants were classified as per American College of Medical Genetics 2015 guidelines and pathogenic (P)/likely pathogenic (LP) variants were considered causative.
There were 77 index cases (male =73%). Median age at diagnosis was 48 months (IQR 18.5 to 108 months). At recruitment, the number of children in each clinical group was as follows: distal renal tubular acidosis (dRTA) = 25; Bartter syndrome = 18; isolated hypophosphatemic rickets (HP) = 6; proximal tubular dysfunction (pTD) = 12; nephrogenic diabetes insipidus (NDI) = 6; kidney stone/nephrocalcinosis (NC) = 6; others = 4. We detected 55 (24 novel) P/LP variants, providing genetic diagnoses in 54 children (70%). The diagnostic yield of WES was highest for NDI (100%), followed by HP (83%; all X-linked HP), Bartter syndrome (78%), pTD (75%), dRTA (64%), and NC (33%). Molecular testing had a definite impact on clinical management in 24 (31%) children. This included revising clinical diagnosis among 14 children (26% of those with a confirmed genetic diagnosis and 18% of the overall cohort), detection of previously unrecognized co-morbidities among 8 children (sensorineural deafness n = 5, hemolytic anemia n = 2, and dental changes n = 1) and facilitating specific medical treatment for 7 children (primary hyperoxaluria n = 1, cystinosis n = 4, tyrosinemia n = 2).
WES is a powerful tool in the diagnosis and management of children with inherited tubulopathies in the Indian population.
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We acknowledge the contributions of the patients and their families for participating in the study.
Medgenome Labs Private Limited has partially funded the genetic tests.
Ethical approval was obtained from the Institute of Child Health Ethics Committee, Kolkata, India.
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Sinha, R., Pradhan, S., Banerjee, S. et al. Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study. Pediatr Nephrol 37, 1811–1836 (2022). https://doi.org/10.1007/s00467-021-05388-y