Abstract: SA-PO813
Large-Scale Exome Sequencing Analysis Implicates FOXQ1, FOXI2, EXOSC2, and MMP15 as Candidate Genes for Human Congenital Obstructive Uropathy
Session Information
- Genetic Diseases: Glomerulopathies - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Ke, Juntao, Columbia University, New York City, New York, United States
- Lim, Tze Yin, Columbia University, New York City, New York, United States
- Gupta, Yask, Columbia University, New York City, New York, United States
- Povysil, Gundula, Columbia University, New York City, New York, United States
- Jin, Gina, Columbia University, New York City, New York, United States
- Martino, Jeremiah, Columbia University, New York City, New York, United States
- Scolari, Francesco, Universita degli Studi di Brescia, Brescia, Lombardia, Italy
- Tasic, Velibor, Medical Faculty of Skopje, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
- Mendelsohn, Cathy L., Columbia University Irving Medical Center, New York, New York, United States
- Gharavi, Ali G., Columbia University, New York City, New York, United States
- Sanna-Cherchi, Simone, Columbia University, New York City, New York, United States
Background
Congenital obstructive uropathy (COU) is the most frequent urinary tract anomaly occurring in up to 2% of pregnancies, constituting a leading cause of pediatric chronic kidney disease. The genetic causes of COU are not well understood and remain to be deciphered.
Methods
We conducted an exome sequencing (ES) study on 880 COU cases, encompassing three main classes of congenital urinary obstructions: a) Ureteropelvic Junction Obstruction (UPJO; N=331), b) Ureterovesical Junction Obstruction / megaloureter (UVJO; N=188), and c) COU not otherwise specified (COU-NOS; N=361). To investigate the excess burden of rare coding variants on COU, we performed exome-wide collapsing analysis comparing the above 880 cases and 16,135 population controls with ES data using 4 main genetic models (3 dominant and one recessive). Analyses were conducted on the entire dataset and then again after removal of cases harboring diagnostic/pathogenic Mendelian mutations and structural variants. Study-wise exome-wide significant threshold was set at 1.25 x 10-6.
Results
In the analysis on the entire cohort of 880 COU cases, the top signal was for FOXQ1 in the dominant ultrarare model from European population (P= 8.49 × 10-6; OR= infinite). The signal improved after removal of solved cases, exceeding exome-wide significance (P= 7.64 × 10-7; OR= infinite), and supporting candidacy for this gene. Moreover, Foxq1 is specially expressed in the mouse developing ureteric buds, ureteric epithelium cells of fetal mouse and human urinary tracts. From the subtype analysis, we found the following suggestive signals: EXOSC2 (P= 2.96 × 10-5; OR= infinite) and FOXI2 (P= 5.52 × 10-5; OR= 82.63) for UPJO; MMP15 (P= 2.56 × 10-5; OR= 21.93) for UVJO.
Conclusion
These findings expand and deepen our understanding of the genetic underpinning of COU, identify novel candidate genes, and highlight the high genetic heterogeneity of disease. We are currently pursuing these findings using human and mouse derived urinary tract enriched organoid systems.
Funding
- Other NIH Support