Abstract: PO1991
Genetic Testing and Biomarkers as Predictive Tools for Congenital Anomalies of Kidney and Urinary Tract (CAKUT)
Session Information
- Pediatric Nephrology: Genetics, Kidney Stones, Quality Improvement, and Case Reports
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1700 Pediatric Nephrology
Authors
- Harris, Meredith, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Erkan, Elif, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Kaufman, Kenneth, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Background
Cincinnati Children’s Hospital is 1 of ~5 centers offering fetal interventions (FI) (amnioinfusions/amnioshunts) & infant hemodialysis (HD) for oligo/anhydramnios (OA), increasing survival from 17 to 50%. As a result of this unique surviving Congenital Anomalies of Kidney & Urinary Tract (CAKUT) population, more investigation into genetics & biomarkers in severe CAKUT needs to be performed, particularly in our growing bilateral multicystic dysplastic kidney (bMCDK) population (fatal at most centers). We hypothesize identification of novel genetic mutations & biomarkers will aid in determination of the clinical course of infants & mechanisms of nephrogenesis.
Methods
Inclusion criteria for severe CAKUT are women undergoing FI for OA or infants starting HD by 1 month of life. We obtained amniotic fluid (AF) during FI and blood from the mother, father, & infant for trios whole exome sequencing (WES). We performed ELISA testing on AF of 4 renal tubular biomarkers produced by fetal kidneys and validated in AF (NGAL, Cystatin c, Uromodulin and ET-1). Controls are 2nd trimester AF from infants without CAKUT.
Results
We enrolled 18 families-6 with bMCDK & obtained 8 AF samples (2 bMCDK). We performed WES on 5 trios (4 bMCDK) & 3 singletons (1 bMCDK). We identified 4 strong candidate genes (Table).
Biomarker testing included 8 AF samples & 10 controls. All 4 biomarkers are significantly lower in severe CAKUT than controls & are lower in bMCDK than bladder obstruction, likely as the bMCDK population has less renal endowment. Biomarkers are lower in those with intrauterine demise compared to liveborn.
Conclusion
In patients with severe CAKUT, we detected 4 strong candidate genes, 3 implicated in embryo development. This population is enriched for genetic variants, likely due to severity of presentation. We validated 4 biomarkers in AF with correlations to diagnosis & survival. WES & biomarker testing are promising techniques to predict the course of severe CAKUT prenatally. Our goal is to develop a polygenic risk score to predict disease severity in utero based on genetic & biomarker data in this unique population.
Genetic Variants in Bilateral MCDK Families
Gene | Chromosome | Variant | MCDK Family | Variant Frequency | Predicted Tolerance | Pathway | Gene Function | Syndromes affiliated with gene | Potential Biomarkers |
FRAS1 | 4 | G to A SNV | F1, F2 | 0.0037% | 1/5 | Integrin | Organogenesis | Fraser Syndrome | integrin α3β1 |
NSUN7 | 2 | De novo frameshift | F2 | N/a | N/a | RNA methylation transferase | Mitochondrial rRNA processing | Familial restrictive cardiomyopathy | None |
MTMR3 | 22 | C to T SNV | F3 | 0.0000040% | 2/5 | Protein Tyrosine Phosphatase, mTOR | Cilia Signaling, Autophagy | Charcot-Marie-Tooth, Lupus Nephritis, IgA nephropathy | Low molecular weight protein-tyrosine phosphatase |
CEP162 | 6 | A to G SNV | F1, F2 | 0.0009% | 1/5 | Axonemal Microtubule Binding | Ciliogenesis, Organelle Biogenesis | Seckel Syndrome, Orofacial Digital Syndrome | None |
Funding
- Other NIH Support