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

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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.

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Acknowledgements

We acknowledge the contributions of the patients and their families for participating in the study.

Funding

Medgenome Labs Private Limited has partially funded the genetic tests.

Author information

Authors and Affiliations

  1. Institute of Child Health, Kolkata, India

    Rajiv Sinha, Sushmita Banerjee, Shakil Akhtar & Surupa Basu

  2. Apollo Hospital, Kolkata, India

    Rajiv Sinha & Amitava Pahari

  3. SVPPGIP & SCB Medical College, Cuttack, India

    Subal Pradhan & Snehamayee Nayak

  4. Calcutta Medical and Research Institute, Kolkata, India

    Sushmita Banerjee

  5. Renowell Clinic and Pratiksha Hospital, Gauhati, India

    Afsana Jahan

  6. North Bengal Medical College, Darjeeling, India

    Sumantra Raut

  7. Neotia Getwel Healthcare Center, Siliguri, India

    Prince Parakh

  8. Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Priyanka Srivastava

  9. Medgenome Labs Ltd, Bangalore, India

    S. G. Thenral & V. Ramprasad

  10. Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

    Emma Ashton

  11. UCL Department of Renal Medicine and Renal Unit, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

    Detlef Bockenhauer

  12. Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India

    Kausik Mandal

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  1. Rajiv Sinha
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Contributions

Rajiv Sinha and Kausik Mandal contributed to conceptualization, supervision, writing, and reviewing the manuscript. All authors have contributed to data acquisition, data curation, editing, and final acceptance for submission of the manuscript.

Corresponding author

Correspondence to Kausik Mandal.

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Ethical approval was obtained from the Institute of Child Health Ethics Committee, Kolkata, India.

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Informed consent was obtained from the parents or guardians as well as from the children aged ≥ 13 years.

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All participants and authors consented to publication.

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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

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  • DOI: https://doi.org/10.1007/s00467-021-05388-y

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