High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults

Marguerite Hureaux; Emma Ashton; Karin Dahan; Pascal Houillier; Anne Blanchard; Catherine Cormier; Eugenie Koumakis; Daniela Iancu; Hendrica Belge; Pascale Hilbert; Annelies Rotthier; Jurgen Del Favero; Franz Schaefer; Robert Kleta; Detlef Bockenhauer; Xavier Jeunemaitre; Olivier Devuyst; Stephen B Walsh; Rosa Vargas-Poussou

doi:10.1016/j.kint.2019.08.027

High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults

Kidney Int. 2019 Dec;96(6):1408-1416. doi: 10.1016/j.kint.2019.08.027. Epub 2019 Sep 16.

Authors

Marguerite Hureaux¹, Emma Ashton², Karin Dahan³, Pascal Houillier⁴, Anne Blanchard⁵, Catherine Cormier⁶, Eugenie Koumakis⁶, Daniela Iancu⁷, Hendrica Belge⁸, Pascale Hilbert⁸, Annelies Rotthier⁹, Jurgen Del Favero⁹, Franz Schaefer¹⁰, Robert Kleta¹¹, Detlef Bockenhauer¹¹, Xavier Jeunemaitre¹, Olivier Devuyst¹², Stephen B Walsh¹³, Rosa Vargas-Poussou¹⁴

Affiliations

¹ Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France; Paris Descartes Université, Sorbonne Paris Cité, Paris, France.
² North East Thames Regional Genetics Service Laboratories, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK.
³ Center of Human Genetics, Institut de Pathologie et Génétique, Gosselies, Belgium; Division of Nephrology, Université Catholique de Louvain Medical School, Brussels, Belgium.
⁴ Paris Descartes Université, Sorbonne Paris Cité, Paris, France; Department of Physiological Functional Investigations, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France.
⁵ Paris Descartes Université, Sorbonne Paris Cité, Paris, France; Assistance Publique Hôpitaux des Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Centre d'Investigation Clinique 1418, Paris, France.
⁶ Rheumatology Department, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Reference Center for Rare Calcium and Phosphate Diseases, Paris, France.
⁷ Department of Renal Medicine, University College London, London, UK.
⁸ Center of Human Genetics, Institut de Pathologie et Génétique, Gosselies, Belgium.
⁹ Multiplicom N.V. (a part of Agilent Technologies), Niel, Belgium.
¹⁰ Paediatric Nephrology, Heidelberg University Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany.
¹¹ Department of Renal Medicine, University College London, London, UK; Department of Pediatric Nephrology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK.
¹² Division of Nephrology, Université Catholique de Louvain Medical School, Brussels, Belgium; Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), Mechanisms of Inherited Kidney Disorders Group, University of Zurich, Zurich, Switzerland. Electronic address: [email protected].
¹³ Department of Renal Medicine, University College London, London, UK. Electronic address: [email protected].
¹⁴ Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France. Electronic address: [email protected].

PMID: 31672324
DOI: 10.1016/j.kint.2019.08.027

Abstract

Hereditary tubulopathies are rare diseases with unknown prevalence in adults. Often diagnosed in childhood, hereditary tubulopathies can nevertheless be evoked in adults. Precise diagnosis can be difficult or delayed due to insidious development of symptoms, comorbidities and polypharmacy. Here we evaluated the diagnostic value of a specific panel of known genes implicated in tubulopathies in adult patients and compared to our data obtained in children. To do this we analyzed 1033 non-related adult patients of which 744 had a clinical diagnosis of tubulopathy and 289 had a diagnosis of familial hypercalcemia with hypocalciuria recruited by three European reference centers. Three-quarters of our tubulopathies cohort included individuals with clinical suspicion of Gitelman syndrome, kidney hypophosphatemia and kidney tubular acidosis. We detected pathogenic variants in 26 different genes confirming a genetic diagnosis of tubulopathy in 29% of cases. In 16 cases (2.1%) the genetic testing changed the clinical diagnosis. The diagnosis of familial hypercalcemia with hypocalciuria was confirmed in 12% of cases. Thus, our work demonstrates the genetic origin of tubulopathies in one out of three adult patients, half of the rate observed in children. Hence, establishing a precise diagnosis is crucial for patients, in order to guide care, to survey and prevent chronic complications, and for genetic counselling. At the same time, this work enhances our understanding of complex phenotypes and enriches the database with the causal variants described.

Keywords: adults; genetic testing; next-generation sequencing; tubulopathy.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Cohort Studies
Gitelman Syndrome / genetics*
High-Throughput Nucleotide Sequencing
Humans
Hypercalcemia / congenital
Hypercalcemia / genetics*
Hypophosphatemia / genetics*