European Journal of Pediatrics

, Volume 177, Issue 9, pp 1399–1405 | Cite as

Novel and recurrent variants in AVPR2 in 19 families with X-linked congenital nephrogenic diabetes insipidus

  • Shivani Joshi
  • Helene Kvistgaard
  • Konstantinos Kamperis
  • Mia Færch
  • Søren Hagstrøm
  • Niels Gregersen
  • Søren Rittig
  • Jane Hvarregaard ChristensenEmail author
Short Communication


Congenital nephrogenic diabetes insipidus (CNDI) is characterized by the reduced ability of renal collecting duct cells to reabsorb water in response to the antidiuretic effect of vasopressin. Chronic polyuria and polydipsia are the hallmarks of the disease. Approximately 90% of all patients with CNDI have X-linked inherited disease caused by variants in the arginine vasopressin receptor 2 (AVPR2) gene. We present genetic findings in 34 individuals from 19 kindreds including one or more family members with CNDI. Coding regions of AVPR2 were sequenced bi-directionally. We identified eight novel disease-causing variants in AVPR2, p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro in nine kindreds. In all three families with more than one affected individual, the novel variants segregated with the disease. We also identified eight recurrent disease-causing variants, p.Val88Met, p.Leu111Valfs*80, p.Arg113Trp, p.Tyr124*, p.Ser167Leu, p.Thr207Asn, p.Arg247Alafs*12, and p.Arg337* in ten kindreds. Our findings contribute to the growing list of AVPR2 variants causing X-linked CNDI.

Conclusion: Being a rapid diagnostic tool for CNDI, direct sequencing of AVPR2 should be encouraged in newborns with familial predisposition to CNDI.

What is Known:

Disease-causing variants in AVPR2 cause X-linked congenital nephrogenic diabetes insipidus (CNDI).

DNA sequencing of AVPR2 is rapid, facilitates differential diagnosis, early intervention, and genetic diagnosis thus reducing morbidity in CNDI.

What is New:

We identified eight novel disease-causing variants in AVPR2: p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro, thereby adding to the growing list of AVPR2 disease-causing variants and emphasizing the importance of genetic testing in CNDI.


X-linked CNDI AVPR2 Novel variants Genetic testing 



Aquaporin 2




Arginine-vasopressin receptor 2


Congenital nephrogenic diabetes insipidus


Nonsense-mediated decay


Transmembrane domain


V2 receptor or arginine-vasopressin receptor 2



We would like to thank the patients and their family members for their cooperation. Jane Knudsen, Margrethe Kjeldsen, and Hong Bich Thi Pham are thanked for their technical assistance. We sincerely thank Dr. Gary L. Robertson, Dr. Lene Rytter, Dr. Ekaterini Siomou, Dr. Hans-Henrik Levang, Dr. Hanne Nørgaard, Dr. Elsebet Østergaard, Dr. Kirsten Rasmussen, Dr. Price, Dr. Clayton, Dr. Kay Metcalfe, late Dr. Nana Thrane, Dr. Hamideh Rastkhani, Dr. Kathrina Main, Dr. Sten A. Ivarsson, Dr. Niels Foged, Dr. Joerg Seidel, Dr. Dina Cortes, Dr. Karsten Hjelt, and late Dr. Laszlo Kovacs for clinical referrals of patients included in this article.

Authors’ Contributions

Shivani Joshi—drafting the article and revising it critically for important intellectual content.

Shivani Joshi, Helene Kvistgaard, Konstantinos Kamperis, Mia Færch, Søren Hagstrøm, Niels Gregersen, Søren Rittig, Jane Hvarregaard Christensen—substantial contributions to conception and design, acquisition of data, data analysis and interpretation as well as editing the manuscript.

Jane Hvarregaard Christensen—final approval of the version to be submitted and any revised version.


Familien Hede Nielsens Fond, Denmark, funded the DNA sequence analysis software.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

For this type of study, formal consent is not required. Additionally, the Regional Committee on Biomedical Research Ethics Denmark agreed that ethical approval and consent to participate was not required for the current study, as patients were referred for clinical diagnostic testing by the clinicians.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shivani Joshi
    • 1
  • Helene Kvistgaard
    • 1
  • Konstantinos Kamperis
    • 1
  • Mia Færch
    • 1
  • Søren Hagstrøm
    • 2
  • Niels Gregersen
    • 3
  • Søren Rittig
    • 1
  • Jane Hvarregaard Christensen
    • 1
    • 4
    Email author
  1. 1.Department of Pediatrics and Adolescent Medicine and Department of Clinical MedicineAarhus University HospitalAarhus NDenmark
  2. 2.Department of PediatricsAalborg University HospitalAalborgDenmark
  3. 3.Department of Clinical Medicine - Research Unit for Molecular MedicineAarhus NDenmark
  4. 4.Department of BiomedicineAarhus UniversityAarhus CDenmark

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