Abstract: PO1328
"APOL1-Plus" Genotypes in Patients with CKD
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Raible, Darbey, Natera, Inc., San Carlos, California, United States
- Clark, Dinah, Natera, Inc., San Carlos, California, United States
- Fang, Fang, Fulgent Genetics, Temple City, California, United States
- Xie, Jing, Natera, Inc., San Carlos, California, United States
Background
Inheritance of homozygous or compound heterozygous APOL1 G1 G2 risk alleles is associated with an increased risk of chronic kidney disease (CKD) including focal segmental glomerulosclerosis (FSGS). The APOL1 high-risk genotype (HRG) is not completely penetrant; additional genetic and/or environmental factors are thought to be necessary for the development of CKD. While approximately 10% of individuals with CKD have causal variants when tested with exome-based next generation sequencing (NGS), few reports have examined co-occurrence of APOL1 HRG alongside these variants. Here we examine the co-occurrence of APOL1 HRG and additional genetic diagnoses (“APOL1-plus”) using a broad NGS panel of CKD genes.
Methods
Clinical samples were analyzed via an NGS panel of >380 genes associated with isolated or syndromic CKD. Positive results had one pathogenic (P) or likely pathogenic (LP) variant in an autosomal dominant or X-linked gene, two P/LP variants in an autosomal recessive gene, or presence of two APOL1 risk alleles.
Results
Among 1691 cases with positive results, 25% (n=430) had positive findings in APOL1. Other positive findings included variants in PKD1/2 in 27% (456/1691) of cases, and in COL4A3/4/5 in 22% (379/1691) of cases. Among positive cases, 7% (119/1691) had >1 positive result, including both dual (n=115) and triple diagnoses (n=4). APOL1 HRG was present in 50% (59/119) of cases with multiple diagnoses, accounting for 3.5% of all positive cases and 14% of all APOL1 HRG cases. Among the APOL1-plus cases, second positive findings were observed in COL4A3/4/5 (29%; 17/59), TTR (29%; 17/59), and PKD1/2 (15%; 9/59).
Conclusion
Dual diagnoses comprised 7% of all positive genetic testing results, with APOL1 HRG present in half of these cases. Future studies are needed to understand how multiple genetic diagnoses, including those with APOL1 HRG, impact disease presentation and progression. Dual APOL1 and collagen IV-related diagnoses are of particular interest given the frequency of these glomerulopathies in the CKD population. Genetic testing via broad NGS panels can improve diagnosis and management of CKD and increased testing will contribute to an evolving understanding of genetic etiologies of CKD.