Targeted Exome Sequencing Identifies PBX1 as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract

J Am Soc Nephrol. 2017 Oct;28(10):2901-2914. doi: 10.1681/ASN.2017010043.

Laurence Heidet ¹ ², Vincent Morinière ¹ ³, Charline Henry ⁴ ⁵, Lara De Tomasi ⁴ ⁵ ⁶, Madeline Louise Reilly ⁴ ⁵ ⁶, Camille Humbert ⁴ ⁵, Olivier Alibeu ⁷, Cécile Fourrage ³ ⁸, Christine Bole-Feysot ⁷, Patrick Nitschké ⁸, Frédéric Tores ⁸, Marc Bras ⁸, Marc Jeanpierre ⁵ ⁹, Christine Pietrement ¹⁰, Dominique Gaillard ¹¹, Marie Gonzales ¹², Robert Novo ¹³, Elise Schaefer ¹⁴, Joëlle Roume ¹⁵, Jelena Martinovic ¹⁶, Valérie Malan ¹⁷, Rémi Salomon ¹ ² ⁴ ⁵, Sophie Saunier ⁴ ⁵, Corinne Antignac ³ ⁴ ⁵, Cécile Jeanpierre ¹⁸ ⁵

Affiliations

1 Assistance Publique - Hôpitaux de Paris, Centre de référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.
2 Assistance Publique - Hôpitaux de Paris, Service de Néphrologie Pédiatrique.
3 Assistance Publique - Hôpitaux de Paris, Département de Génétique, and.
4 Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Laboratory of Hereditary Kidney Diseases.
5 Paris Descartes Sorbonne Paris Cité University, Paris, France.
6 Paris Diderot University, Paris, France.
7 Genomic Platform, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Paris Descartes Sorbonne Paris Cité University, and.
8 Bioinformatic Plateform, Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France.
9 Assistance Publique - Hôpitaux de Paris, Département de Génétique, Hôpital Cochin, Paris, France.
10 Unité de néphrologie pédiatrique and.
11 Service de Génétique clinique, Centre Hospitalo-Universitaire de Reims, Reims, France.
12 Assistance Publique - Hôpitaux de Paris, Département de Génétique Médicale, Hôpital Armand Trousseau and Université Pierre et Marie Curie, Paris, France.
13 Centre Hospitalo-Universitaire de Lille, Hôpital Jeanne de Flandre, Service de Néphrologie Pédiatrique, Lille, France.
14 Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
15 Unité de Génétique Médicale, Centre Hospitalier Intercommunal Poissy, St. Germain en Laye, Poissy, France; and.
16 Assistance Publique - Hôpitaux de Paris, Unit of Fetal Pathology, Antoine Béclère Hospital, Clamart, France.
17 Assistance Publique - Hôpitaux de Paris, Service de Cytogénétique, Hôpital Universitaire Necker-Enfants malades, Paris, France.
18 Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Laboratory of Hereditary Kidney Diseases, [email protected].

PMID: 28566479 DOI: 10.1681/ASN.2017010043

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified. However, despite high-throughput sequencing studies, the cause of the disease remains unknown in most patients, and several studies support more complex inheritance and the role of environmental factors and/or Epigenetics in the pathophysiology of CAKUT. Here, we report the targeted exome sequencing of 330 genes, including genes known to be involved in CAKUT and candidate genes, in a cohort of 204 unrelated patients with CAKUT; 45% of the patients were severe fetal cases. We identified pathogenic mutations in 36 of 204 (17.6%) patients. These mutations included five de novo heterozygous loss of function mutations/deletions in the PBX homeobox 1 gene (PBX1), a gene known to have a crucial role in kidney development. In contrast, the frequency of SOX17 and DSTYK variants recently reported as pathogenic in CAKUT did not indicate causality. These findings suggest that PBX1 is involved in monogenic CAKUT in humans and call into question the role of some gene variants recently reported as pathogenic in CAKUT. Targeted exome sequencing also proved to be an efficient and cost-effective strategy to identify pathogenic mutations and deletions in known CAKUT genes.

Keywords

genetic renal disease; genetics and development; kidney development.

Name
Email *

	Sorry, but the email address you supplied was invalid.