ESPN 50th Annual Meeting

ESPN 2017

Targeted exome sequencing of a cohort of 204 patients identifies PBX1 as a novel gene involved in monogenic CAKUT
Heidet Laurence 1 Morinière Vincent Henry Charline De Tomasi Lara Fourrage Cécile Pietrement Christine Gaillard Dominique Novo Robert Martinovic Jelena Malan Valérie Salomon Remi Saunier Sophie Antignac Corinne Jeanpierre Cécile

1- APHP, Pediatric Nephrology Department, Reference Center MARHEA, Necker Hospital, Paris, France
2- APHP, Genetic Department, Necker Hospital, Paris
3- Inserm UMR1163, Imagine Institute, Paris Descartes University, Paris
4- Pediatric Nephrology and Genetic Departments, CHU Reims, France
5- Pediatric Nephrology Department, CHU Lille, France
6- Unit of Fetal Pathology, Antoine Béclère Hospital, Clamart, France
7- Cytogenetic Department, Necker Hospital, Paris

CAKUT (Congenital Anomalies of the Kidney and Urinary Tract) are major causes of chronic kidney disease in children. They are phenotypically and genetically heterogeneous diseases. Monogenic causes of CAKUT in humans, as well as in mouse, have been identified, with more than 50 genes reported as mutated, mostly in syndromic forms. Most of the mutations are heterozygous, with autosomal dominant inheritance and variable expressivity. The most frequently mutated genes are HNF1B, PAX2, EYA1 and SIX1, all encoding transcription factors. Many of the other genes are mutated in only few patients and their implication is sometimes elusive.


Material and methods:

We developed a targeted exome sequencing strategy (« cakutome ») focusing on 330 genes, either known to be involved in CAKUT or being candidates (genes whose knock-out in mouse lead to CAKUT, genes involved in cellular processes/signaling pathways relevant for kidney development), in a cohort of 204 unrelated CAKUT cases, 45% of which were severe fetal cases.



This approach allowed us to identify heterozygous loss-of-function mutations/deletions in PBX1 (Pre-B-Cell Leukemia Transcription Factor 1), a gene reported to play a crucial role in kidney development in the mouse, in 5 cases with syndromic (4 patients) or isolated (1 fetus) renal hypodysplasia. We showed that all the mutations (including a nonsense, a frameshift and a splice mutation and 2 large deletions encompassing PBX1 and additional genes) occurred de novo. PBX1 is thus a novel gene involved in monogenic CAKUT in humans.

We also identified pathogenic mutations and copy number variations in known CAKUT genes : heterozygous mutations/deletions in HNF1B (9 cases), PAX2 (9 cases), EYA1 (5 cases), GATA3 (3 cases), ANOS1 (2 cases) and CHD7 (1 cases), and biallelic mutations in KIF14 (2 fetuses with renal hypodysplasia and microcephaly), thus providing a genetic diagnosis in 15% of the cohort. The rate of deletion (removing one or several exons) was quite high (47%).

Our results also led us to call into question the role of some variations in SOX17 and DSTYK recently reported as pathogenic in CAKUT.



This targeted exome sequencing strategy thus proved to be efficient and cost-effectiv, and allowed the identification of PBX1 as a novel CAKUT gene.