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Variants in genes coding for collagen type IV α-chains are frequent causes of persistent, isolated hematuria during childhood

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Abstract

Background

Children with persistent, isolated microscopic hematuria typically undergo a limited diagnostic workup and are monitored for signs of kidney disease in long-term longitudinal follow-up, which can delay diagnosis and allow disease progression in some cases.

Methods

To determine the clinical utility of genetic screening in this population, we performed targeted genetic testing using a custom, 32-gene next-generation sequencing panel for progressive kidney disease on children referred to the Texas Children’s Hospital Pediatric Nephrology clinic for persistent, microscopic hematuria (n = 30; cohort 1). Patients with microscopic hematuria identified by urinalysis on at least two separate occasions were eligible for enrollment, but those with other evidence of kidney disease were excluded. Results were analyzed for sequence variants using the American College of Medical Genetics and Genomics (ACMG) guideline for data interpretation and were validated using a secondary analysis of a dataset of children with hematuria and normal kidney function who had undergone genetic testing as part of an industry-sponsored program (cohort 2; n = 67).

Results

In cohort 1 33% of subjects (10/30) had pathogenic or likely pathogenic (P/LP) variants in the type IV collagen genes (COL4A3/A4/A5), and 10% (3/30) had variants of uncertain significance in these genes. The high diagnostic rate in type IV collagen genes was confirmed in cohort 2, where 27% (18/67) of subjects had P/LP variants in COL4A3/A4/A5 genes.

Conclusions

Children with persistent, isolated microscopic hematuria have a high likelihood of having pathogenic variants in type IV collagen genes and genetic screening should be considered.

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Acknowledgements

The authors would like to acknowledge all the patients and their family members who participated in this research study. We would like to thank Reata Pharmaceuticals Inc. for sharing the results of cohort 2. The authors would additionally like to thank all referring physicians from the Division of Pediatric Nephrology at Baylor College of Medicine (BCM) and Texas Children’s Hospital (TCH), as well as the staff of the BCM Human Genome Sequencing Center, especially Dr. Richard Gibbs, director, and Donna Muzny, for their contributions.

Funding

This study was supported by start-up funding from the Division of Pediatric Nephrology at Baylor College of Medicine and Texas Children’s Hospital and by funding from the Baylor College of Medicine Precision Medicine/Population Health Initiative. It was completed in collaboration with Reata Pharmaceuticals Inc., by which A. R. W. is employed.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Nephrology, Baylor College Medicine, Houston, TX, 77030, USA

    Joseph L. Alge, Nasim Bekheirnia, Michael C. Braun & Mir Reza Bekheirnia

  2. Reata Pharmaceuticals Inc, Plano, TX, 75024, USA

    Alexandra R. Willcockson

  3. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Xiang Qin & Steven E. Scherer

  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Steven E. Scherer & Mir Reza Bekheirnia

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  1. Joseph L. Alge
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Correspondence to Mir Reza Bekheirnia.

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Alge, J.L., Bekheirnia, N., Willcockson, A.R. et al. Variants in genes coding for collagen type IV α-chains are frequent causes of persistent, isolated hematuria during childhood. Pediatr Nephrol 38, 687–695 (2023). https://doi.org/10.1007/s00467-022-05627-w

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