Abstract: TH-PO457
Getting the Full Picture: Identifying Cases with Multiple Genetic Diagnoses Using Comprehensive Renal Gene Testing
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania 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
- Hendricks, Emily, Natera, Inc., Austin, Texas, United States
- Pitman, Tessa R., Natera, Inc., Austin, Texas, United States
- Westemeyer, Margaret, Natera, Inc., Austin, Texas, United States
- Anand, Akash, Natera, Inc., Austin, Texas, United States
- Hager, Megan M., Natera, Inc., Austin, Texas, United States
- Punj, Sumit, Natera, Inc., Austin, Texas, United States
- Stein, Quinn P., Natera, Inc., Austin, Texas, United States
Background
Comprehensive genetic testing can provide genetic diagnoses for kidney disease of unknown etiology and those with unexpected phenotypes due to multiple genetic causes.
Methods
Analysis of 42,221 samples tested with the Renasight™ test was performed to identify cases with diagnostic findings in ≥ 2 genes. The cases were categorized based on: 1) disease penetrance: high (variants are expected to cause the condition) or susceptible (variants provide risk for disease development) and/or 2) disease phenotypic presentation: a) distinct phenotypes (2 conditions with dissimilar symptoms), b) same phenotype (2 distinct conditions with the same symptoms), c) combined phenotype (2 distinct genes that interact to cause the same disease (Digenic)).
Results
A total of 818 cases with multiple positive results spanning 130 genes (787 dual and 31 triple) were found, accounting for 7.7% of all tests with a positive result. Of the 369 different gene combinations identified, 274 occurred only once. The most common positive gene result was APOL1 (344, 42.1%), among which, additional positive findings included: high penetrance genes with expected distinct phenotypes (28.9%), TTR (associated with cardiac amyloidosis; 9.5%) and other susceptibility genes (1.2%). Multiple positive findings among the non-APOL1 cases (56.4%) included those with 2 high penetrance genes that cause distinct phenotypes (35.3%), cases with both a high penetrance gene and a susceptibility gene (8.91%), and cases with a TTR finding and a second high penetrance gene (7.2%). Digenic findings comprised 3.8% of all multiple positive cases and those with two separate gene findings that independently cause the same phenotype comprised 1.2% (Table).
Conclusion
We found that 7.7% of patients with genetic kidney disease had multiple etiologies that encompassed a wide range of genes and combinations demonstrating that comprehensive genetic testing is crucial for identifying the full range of genetic causes of kidney diseases that may be missed by traditional testing methods.
Table: Summary of the dual and triple positive findings results