Abstract: PO1634
Generating Monogenic CAKUT Candidate Genes from Existing Single-Cell Transcriptomics Data of Human Fetal Kidney
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Schierbaum, Luca M., Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Schneider, Sophia, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Buerger, Florian, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Seltzsam, Steve, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Wang, Chunyan, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Zheng, Bixia, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Wu, Chen-Han Wilfred, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Nakayama, Makiko, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Shril, Shirlee, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, United States
Background
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most frequent birth defect and the most frequent cause of chronic kidney disease in the first 3 decades of life. Discovery of >34 monogenic causes of human CAKUT has helped mapping pathogenic pathways of CAKUT in humans (JASN 29:36, 2018).
We hypothesized that genes specific to pathogenic pathways of CAKUT may show a temporo-spatial single-cell mRNA expression pattern in human fetal kidney tissue, and that highly expressed genes may represent novel CAKUT candidate genes.
Methods
First, we evaluated 34 monogenic human genes involved in CAKUT pathways for clustering in a temporo-spatial mRNA expression pattern by using the single-cell mRNA sequencing derived dataset of human fetal kidney at developmental week 17 (Hochane, PLoS Biol 21:17, 2019) and week 16 (Lindstrom, Dev Cell 45:651, 2018).
86 novel CAKUT candidate genes were generated by Whole Exome Sequencing (WES).
Results
The evaluation of the 34 known CAKUT pathway genes showed that genes involved in the FRAS/FREM, RA signaling and BMP signaling pathways did not cluster in either mRNA dataset. However, genes involved in the pathogenesis of branchiootorenal (BOR) syndrome (EYA1, SIX1, SIX2, SIX5) clustered in nephron progenitor cells (NPCs) in both datasets. We therefore concluded that NPCs are relevant for CAKUT pathogenesis.
Based on the outcome of this first step, to prioritize potential novel CAKUT genes, we then generated and overlapped two lists of independent candidate genes: i) 86 novel single CAKUT candidate genes derived from WES in 1,380 patients and ii) the 100 highest expressed genes in each NPC type a, b, c and d according to Hochane (PLoS Biol 21:17, 2019).
This overlap of lists i) and ii) resulted in one gene KIF19 (Kinesin Family Member 19), which is therefore considered as a novel candidate gene for human CAKUT.
Conclusion
Genes of the BOR pathway are co-expressed in a temporo-spatial way and expressed in a time-specific and cell-type-specific manner throughout human renal development. Single-cell mRNA expression data from human fetal kidney can be used to prioritize WES-derived CAKUT candidate genes.
Funding
- Other NIH Support