Abstract: PO1656
Whole-Exome Sequencing as a Predictive Tool for Severe CAKUT
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
- 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
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) represent about 1% of births, with about 20% secondary to genetic causes. The Cincinnati Fetal Center is one of the few centers worldwide offering fetal interventions including amnioinfusion and for infants with oligo/anhydramnios. As these infants are phenotypically severe, we predict they will be genetically enriched. We hypothesize that identifying novel genetic variants in infants with CAKUT will aid in determination of clinical course and improve parental counseling.
Methods
We collected blood from infants whose mothers underwent fetal interventions for oligo/anhydramnios for the purpose of Whole Exome Sequencing as well as blood samples from parents for trios testing.
Results
We completed variant calling for 2 singletons and 1 maternal sample. Both patients’ mothers underwent multiple amnioinfusions, and the patients required initiation of RRT within week 1 of life. In both patients, we identified a nonsynonymous SNV of HSPG2 on chromosome 1. HSPG2 encodes for perlecan, which has a role in renal embryogenesis, specifically the maturation of the epithelial and mesenchymal tissues of the kidney. We identified a rare heterozygous variant found in 0.28% of the population in 1 patient. In the other patient, we identified 2 variants, which form a state of compound heterozygosity. We found a rare heterozygous nonsynonymous SNV mutation in T-Box Transcription Factor-18 (TBX18) in 1 sample. TBX18 is imperative for the development of ureteric mesenchyme and is expressed in the renal capsule and glomerular mesangial cells. This patient had bilateral VUR and dysplastic kidneys. The other patient had a rare heterozygous nonsynonymous SNV in the transcriptional repressor GLI3 which is implicated in renal morphogenesis. Variants in GLI3 have been described in renal dysplasia and aplasia. This patient was born with bilateral multicystic dysplastic kidneys.
Conclusion
In our pilot data of WES of 2 singletons and 1 maternal sample, we report 3 candidate genes, HSPG2, TBX18, and GLI3, all of which are necessary for renal and urinary tract development, specifically glomerular and ureteric development and transcriptional regulation. In a small cohort, we demonstrate that WES of a severely affected population provides insight into the molecular mechanisms underlying CAKUT, which can aid in prognosis and parental counseling in the future.
Funding
- Other NIH Support