Abstract: PO1523
Whole-Exome Sequencing in 97 Families with Renal Ciliopathies Reveals a Causative Mutation in a Known Kidney Disease Gene in 62% and Identifies Potential Novel Causative Genes
Session Information
- Cystic Kidney Diseases: Mechanisms, Genetics, and Treatment
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Deutsch, Konstantin, Boston Children's Hospital, Department of Medicine, Boston, Massachusetts, United States
- Klambt, Verena, Boston Children's Hospital, Department of Medicine, Boston, Massachusetts, United States
- Kitzler, Thomas Michael, Boston Children's Hospital, Department of Medicine, Boston, Massachusetts, United States
- Jobst-Schwan, Tilman, Boston Children's Hospital, Department of Medicine, Boston, Massachusetts, United States
- Shril, Shirlee, Boston Children's Hospital, Department of Medicine, Boston, Massachusetts, United States
- Mane, Shrikant M., Yale University School of Medicine, New Haven, Connecticut, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Department of Medicine, Boston, Massachusetts, United States
Background
Nephronophthisis-related ciliopathies (NPHP-RC) represent the most frequent genetic cause of end-stage renal disease in the first three decades of life. Affected children present with increased echogenicity and/or cysts on renal ultrasound. As mutations in 96 recessive genes have been identified as disease-causing (Kidney Int 95:914, 2019), whole exome sequencing (WES) represents the best approach for the identification of the causative mutation (Nephrol Dial Transplant 31:1802, 2016). In a previous study of consanguineous or familial cases of NPHP, we identified causative mutations in 63% of all patients (Kidney Int 89:468, 2016) by WES.
Methods
To reveal the percentage of causative mutations in NPHP-RC and to identify potential novel disease genes, we evaluated WES data from 97 families with childhood-onset NPHP-RC for causative mutations in 178 monogenic chronic kidney disease genes. Clinical inclusion criteria were increased renal echogenicity or identification of ≥ 2 renal cysts on renal ultrasound.
Results
In 60 out of 97 families (62%), we identified a mutation in a known monogenic kidney disease gene as causative for the phenotype. Out of these, 47 families harboured mutations in one of the known ciliopathy genes. 13 families were diagnosed for a disease that phenocopies NPHP-RC. Amongst these, CAKUT represented the most frequent phenocopy disease (7/13 families), followed by Alport syndrome, metabolic diseases and nephrocalcinosis (2/13 families each). In 10 families, in which a mutation in known disease genes was excluded, we identified a biallelic mutation in a potential novel causative gene candidate.
Conclusion
By whole exome sequencing we identified a disease-causing mutation in 62% of families with a diagnosis of NPHP based on renal ultrasound and identified 10 potential novel causative gene candidates.
Funding
- NIDDK Support