RT Journal Article SR Electronic T1 PBX1 haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 502 OP 510 DO 10.1136/jmedgenet-2016-104435 VO 54 IS 7 A1 Le Tanno, Pauline A1 Breton, Julie A1 Bidart, Marie A1 Satre, Véronique A1 Harbuz, Radu A1 Ray, Pierre F A1 Bosson, Caroline A1 Dieterich, Klaus A1 Jaillard, Sylvie A1 Odent, Sylvie A1 Poke, Gemma A1 Beddow, Rachel A1 Digilio, Maria Christina A1 Novelli, Antonio A1 Bernardini, Laura A1 Pisanti, Maria Antonietta A1 Mackenroth, Luisa A1 Hackmann, Karl A1 Vogel, Ida A1 Christensen, Rikke A1 Fokstuen, Siv A1 Béna, Frédérique A1 Amblard, Florence A1 Devillard, Francoise A1 Vieville, Gaelle A1 Apostolou, Alexia A1 Jouk, Pierre-Simon A1 Guebre-Egziabher, Fitsum A1 Sartelet, Hervé A1 Coutton, Charles YR 2017 UL http://jmg.bmj.com/content/54/7/502.abstract AB Background Congenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion.Methods We describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA). Clinical features were collected, especially the renal and urinary tract phenotype, and extrarenal features. We characterised PBX1 expression and localisation in fetal and adult kidneys using quantitative RT-PCR and immunohistochemistry.Results We defined a 276-kb minimal common region (MCR) that only overlaps with the PBX1 gene. All eight patients presented with syndromic CAKUT. CAKUT were mostly bilateral renal hypoplasia (75%). The most frequent extrarenal symptoms were developmental delay and ear malformations. We demonstrate that PBX1 is strongly expressed in fetal kidneys and brain and expression levels decreased in adult samples. In control fetal kidneys, PBX1 was localised in nuclei of medullary, interstitial and mesenchymal cells, whereas it was present in endothelial cells in adult kidneys.Conclusions Our results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model. Correct PBX1 dosage appears to be critical for normal nephrogenesis and seems important for brain development in humans. CMA should be recommended in cases of fetal renal anomalies to improve genetic counselling and pregnancy management.