Abstract: FR-PO666
Population Frequency of Common Genetic Causes of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
Session Information
- Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
October 25, 2024 | Location: Exhibit Hall, 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
- Huang, Mary, The University of Melbourne, Melbourne Medical School, Melbourne, Victoria, Australia
- Savige, Judith A., The University of Melbourne Faculty of Medicine Dentistry and Health Sciences, Melbourne, Victoria, Australia
Background
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is the leading cause of kidney failure in children. Imaging suggests that CAKUT affects one in 200 newborns and genetic causes are estimated in 20% of these or one in 1000. Six genes are commonly affected and, while more than 250 have been reported, most are only found in individual families. This study determined a more accurate population frequency for genetic causes of CAKUT from the number of predicted pathogenic variants in the commonest CAKUT genes and from pathogenic variants found in variant databases.
Methods
HNF1B, SALL1, EYA1, PBX1, GATA3, PAX2 variants were downloaded from gnomAD v.2.1, and annotated in ANNOVAR. Structural and null variants were considered pathogenic and missense variants were assessed for pathogenicity based on their rarity, scores in PP2, SIFT and MT, and whether they affected a residue conserved in vertebrates. This approach for predicted pathogenic missense variants in HNF1B had a sensitivity of 80% and specificity of 63%. The population frequencies for the 6 genes were then compared with those in the control gnomAD subset, and with the variants classified as pathogenic in ClinVar, LOVD or HGMD.
Results
Overall, predicted pathogenic variants in the 6 CAKUT genes affected one in 230 of the gnomAD population and one in 270 controls. The population frequency of structural and null variants alone was one in 1642. Predicted pathogenic variants causing CAKUT were least common in Ashkenazi people (one in 864) and Finns (one in 837). The population frequencies for all pathogenic variants were one in 1263 for ClinVar, one in 437 for LOVD, one in 40 for HGMD.
Conclusion
Genetic forms of CAKUT resulting from predicted pathogenic variants in the most frequently affected genes are found more often than previously suspected and may represent the major cause of CAKUT rather than environmental factors.