Abstract: SA-OR048
Large-Scale CNV Analysis Provides Insight into the Genomic Architecture of Congenital Anomalies of the Kidney and Urinary Tract
Session Information
- Pediatric Nephrology and Developmental Biology
November 04, 2017 | Location: Room 285, Morial Convention Center
Abstract Time: 05:54 PM - 06:06 PM
Category: Developmental Biology and Inherited Kidney Diseases
- 403 Pediatric Nephrology
Authors
- Verbitsky, Miguel, Columbia University, New York, New York, United States
- Westland, Rik, Vrije Universiteit University Hospital Amsterdam, Amsterdam, Netherlands
- Perez, Alejandra, Columbia University, New York, New York, United States
- Krithivasan, Priya, Columbia University, New York, New York, United States
- Fasel, David, Columbia University, New York, New York, United States
- Sampson, Matt G., University of Michigan, Ann Arbor, Michigan, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
- Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy
- Van Wijk, Joanna, Vrije Universiteit University Hospital Amsterdam, Amsterdam, Netherlands
- Gesualdo, Loreto, University of Bari, Altamura, BARI, Italy
- Jeanpierre, Cecile, Inserm UMR1163/Imagine Institute, Paris, France
- Saraga, Marijan, University Hospital in Split, Split, Croatia
- Simões e silva, Ana cristina, UFMG, Brazil, Belo Horizonte, Brazil
- Furth, Susan L., The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
- Wong, Craig S., UNM, Albuquerque, New Mexico, United States
- Materna-Kiryluk, Anna, Poznan University of Medical Sciences, Poznan, Poland
- Kiryluk, Krzysztof, Columbia University, New York, New York, United States
- Hakonarson, Hakon, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
- Ghiggeri, Gian Marco, G. Gaslini Children Hospital, Genoa, Italy
- Zhang, Feng, Fudan University, Shanghai, China
- Papaioannou, Virginia, Columbia University, New York, New York, United States
- Mendelsohn, Cathy, Columbia University, New York, New York, United States
- Gharavi, Ali G., Columbia University, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
Background
Copy number variations (CNVs) play an important role in the pathogenesis of human birth defects.
Methods
We performed a genome-wide CNV study in 2,824 cases compared to 21,498 controls to elucidate the genomic landscape of disease across the whole phenotypic spectrum of CAKUT.
Results
CAKUT cases carried a significant increased burden of rare CNVs and were highly enriched for known genomic disorders (GD) compared to controls (OR 6.6, P=7.5x10-41). Renal hypodysplasia (RHD) showed the highest enrichment (OR 12.7, P=8.5x10-50), followed by obstructive uropathy (OU; OR 3.5, P=6.0x10-4), and posterior urethral valves (PUV; OR 5.9, P=2.2x10-3). The most frequent GD loci in cases were 17q12 (n=26), 22q11.2 (n=17), the 1q21 (n=10), and 16p11.2 (n=9). While the 17q12, 22q11.2, and 1q21 were specific for RHD, the 16p11.2 showed high pleiotropy. At the loci where deletions were associated to RHD, duplications were associated to PUV or duplicated collecting system.
Deletion mapping and in silico annotation identified TBX6 as a candidate driver gene for CAKUT in the 16p11.2 deletion syndrome. We identified a de novo frameshift mutation in TBX6 in a case with scoliosis and CAKUT. Analysis of mouse models for two different Tbx6 alleles identified highly penetrant CAKUT recapitulating the high pleiotropic effect observed in humans with 16p11.2 deletions.
Conclusion
Our study describes the genomic landscape across the phenotypic spectrum of CAKUT, identifies recurrent CNVs for urinary tract developmental phenotypes and identifies TBX6 as a genetic driver of CAKUT in the 16p11.2 deletion syndrome.
Funding
- NIDDK Support