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Bi-allelic mutations in renin-angiotensin system genes, associated with renal tubular dysgenesis, can also present as a progressive chronic kidney disease

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Abstract

Background

Bi-allelic loss of function variations in genes encoding proteins of the renin-angiotensin system (AGT, ACE, REN, AGTR1) are associated with autosomal recessive renal tubular dysgenesis, a severe disease characterized by the absence of differentiated proximal tubules leading to fetal anuria and neonatal end-stage renal disease.

Case-Diagnosis/Treatment

We identified bi-allelic loss of function mutations in ACE, the gene encoding angiotensin-converting enzyme, in 3 unrelated cases displaying progressive chronic renal failure, whose DNAs had been sent for suspicion of juvenile hyperuricemic nephropathy, nephronophthisis, and cystic renal disease, respectively. In all cases, patients were affected with anemia whose severity was unexpected regarding the level of renal failure and with important polyuro-polydipsia.

Conclusions

Bi-allelic loss of function mutation of ACE can have atypical and sometimes late presentation with chronic renal failure, anemia (out of proportion with the level of renal failure), and polyuro-polydipsia. These data illustrate the usefulness of next generation sequencing and “agnostic” approaches to elucidate cases with chronic kidney disease of unknown etiology and to broaden the spectrum of phenotypes of monogenic renal diseases. It also raises the question of genetic modifiers involved in the variation of the phenotypes associated with these mutations.

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Acknowledgments

We thank patients and families for their participation. We thank Patrick Nitschké from the Bioinformatic Plateform; Paris Descartes Sorbonne Paris Cité University; Imagine Institute, Paris, France; and Cecile Fourrage from the Genetic Department, APHP, Hôpital universitaire Necker-Enfants malades, Paris, France, for their help with NGS.

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Authors and Affiliations

  1. Néphrologie pédiatrique, Centre de Référence maladies rénales rares SORARE, CHU Arnaud de Villeneuve, Montpellier, France

    Marc Fila

  2. APHP, Génétique moléculaire, Centre de Référence MARHEA, Hôpital Universitaire Necker-Enfants malades, Paris, France

    Vincent Morinière & Corinne Antignac

  3. Néphrologie pédiatrique, Centre Hospitalier Universitaire de Caen Normandie, Caen, France

    Philippe Eckart

  4. Néphrologie pédiatrique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    Joelle Terzic

  5. Laboratoire des Maladies rénales héréditaires, Institut Imagine, Inserm U1163, Université de Paris, Paris, France

    Marie-Claire Gubler & Corinne Antignac

  6. APHP, Néphrologie pédiatrique, Centre de Référence MARHEA, Hôpital Universitaire Necker-Enfants malades, 149 rue de Sèvres, 75015, Paris, France

    Laurence Heidet

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  1. Marc Fila
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  2. Vincent Morinière
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  3. Philippe Eckart
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  5. Marie-Claire Gubler
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  7. Laurence Heidet
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Correspondence to Laurence Heidet.

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Fila, M., Morinière, V., Eckart, P. et al. Bi-allelic mutations in renin-angiotensin system genes, associated with renal tubular dysgenesis, can also present as a progressive chronic kidney disease. Pediatr Nephrol 35, 1125–1128 (2020). https://doi.org/10.1007/s00467-020-04524-4

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  • DOI: https://doi.org/10.1007/s00467-020-04524-4

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