Back to Search Start Over

Targeted Exome Sequencing Identifies

Authors :
Laurence, Heidet
Vincent, Morinière
Charline, Henry
Lara, De Tomasi
Madeline Louise, Reilly
Camille, Humbert
Olivier, Alibeu
Cécile, Fourrage
Christine, Bole-Feysot
Patrick, Nitschké
Frédéric, Tores
Marc, Bras
Marc, Jeanpierre
Christine, Pietrement
Dominique, Gaillard
Marie, Gonzales
Robert, Novo
Elise, Schaefer
Joëlle, Roume
Jelena, Martinovic
Valérie, Malan
Rémi, Salomon
Sophie, Saunier
Corinne, Antignac
Cécile, Jeanpierre
Source :
Journal of the American Society of Nephrology : JASN. 28(10)
Publication Year :
2017

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.

Details

ISSN :
15333450
Volume :
28
Issue :
10
Database :
OpenAIRE
Journal :
Journal of the American Society of Nephrology : JASN
Accession number :
edsair.pmid..........876768522bec1ce1cfff7618cae7ffa8