Abstract: FR-PO665
Population Frequency of Genetic Causes of Autosomal Dominant FSGS
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 Faculty of Medicine Dentistry and Health Sciences, Melbourne, Victoria, Australia
- Savige, Judith A., The University of Melbourne Faculty of Medicine Dentistry and Health Sciences, Melbourne, Victoria, Australia
Background
Patients with autosomal dominant (AD) Focal and Segmental Glomerulosclerosis (FSGS) often have pathogenic variants in the Alport genes (COL4A3, 4), or in ACTN4, INF2, PAX2, TRPC6 or WT1. This study determined how often ‘predicted pathogenic’ variants in the commonest genes affected in AD FSGS were found undiagnosed in the normal population.
Methods
Genes were downloaded from gnomAD v2.1 and annotated in ANNOVAR. Structural and null variants were ‘predicted pathogenic’ and missense variants assessed for predicted pathogenicity based on rarity, computational scores, and whether they affected a conserved amino acid. As an example, our approach for predicting pathogenic missense variants in INF2 had a sensitivity of 95% and specificity of 95% when compared with 20 benign and 20 pathogenic variants reported in LOVD. The population frequencies for the genes were then compared with variants classified Pathogenic or Likely pathogenic in ClinVar. (ClinVar variant assessments are likely to be accurate but lists may be incomplete.)
Results
Predicted pathogenic variants (null, structural and missense changes) in COL4A3 and COL4A4 affected about one in 113 individuals. Predicted pathogenic variants in the other genes for AD FSGS affected one in 186 individuals. The number of people with a variant in an AD FSGS gene classified Pathogenic or Likely Pathogenic in Clin Var was much less, corresponding to one in 4711 of the population.
Conclusion
Predicted pathogenic variants in COL4A3 and COL4A4 together are more common than other genes associated with AD FSGS. The true population frequency is likely to be greater than that calculated from variants reported Pathogenic or Likely pathogenic in ClinVar and may be closer to our assessment. However the penetrance of these predicted pathogenic variants for AD FSGS is not known.
Number of people with predicted pathogenic variant in AD FSGS genes
| Total of COL4A3, 4 | ACTN4 | INF2 | PAX2 | TRPC6 | WT1 | Total of other genes | |
| Null and structural variants | 350 (one in 323) | 22 | 24 | 28 | 65 | 109 | 248 (one in 436) |
| Missense variants – our assessment | 649 (one in 174) | 87 | 106 | 48 | 97 | 21 | 359 (one in 301) |
| Total with our assessment | 999 (one in 113) | 109 | 130 | 76 | 162 | 130 | 607 (one in 186) |
| ClinVar | 824 (one in 137) | 2 | 3 | 13 | 2 | 3 | 23 (one in 4711) |