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10.01.2022 | Original Article

Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study

verfasst von: Rajiv Sinha, Subal Pradhan, Sushmita Banerjee, Afsana Jahan, Shakil Akhtar, Amitava Pahari, Sumantra Raut, Prince Parakh, Surupa Basu, Priyanka Srivastava, Snehamayee Nayak, S. G. Thenral, V. Ramprasad, Emma Ashton, Detlef Bockenhauer, Kausik Mandal

Erschienen in: Pediatric Nephrology | Ausgabe 8/2022

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Abstract

Background

Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology.

Methods

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.

Results

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).

Conclusion

WES is a powerful tool in the diagnosis and management of children with inherited tubulopathies in the Indian population.

Graphical abstract

A higher resolution version of the Graphical abstract is available as Supplementary information

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Titel: Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study
verfasst von: Rajiv Sinha
Subal Pradhan
Sushmita Banerjee
Afsana Jahan
Shakil Akhtar
Amitava Pahari
Sumantra Raut
Prince Parakh
Surupa Basu
Priyanka Srivastava
Snehamayee Nayak
S. G. Thenral
V. Ramprasad
Emma Ashton
Detlef Bockenhauer
Kausik Mandal
Publikationsdatum: 10.01.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Nephrology / Ausgabe 8/2022
Print ISSN: 0931-041X
Elektronische ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-021-05388-y

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Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study