Abstract: FR-PO439
Identification of Mutations in an Atypical Focal Segmental Glomerulosclerosis-Causing Gene
Session Information
- Pediatric Nephrology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1102 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Rajashekar, Gaurav, Washington University in St Louis, St Louis, Missouri, United States
- Chen, Ying Maggie, Washington University in St Louis, St Louis, Missouri, United States
Introduction
Focal segmental glomerulosclerosis (FSGS) is a histopathological diagnosis. More than 50 monogenic forms of FSGS have been identified. With broader utilization of genetic sequencing, mutations in genes, not commonly associated with glomerular disease, have been identified in FSGS.
Case Description
Here we present a 29-year old female with an extensive family history of proteinuria on her paternal side (Fig. 1) presenting with proteinuria (urine protein/creatinine ratio 1.7g/g) at the age of 18. Biopsy at that time showed FSGS. She underwent whole exome sequencing which showed variants in RPGRIP1L, p.V682I (heterozygous) and p.I1005V (heterozygous), as well as a variant in CC2D2A, p.A1050V (heterozygous). Although variants in RGRIP1L or CC2D2A have not been associated with FSGS, due to her family history of proteinuria, we performed Sanger sequencing on her family members. Her father, who has proteinuria (without biopsy) carries the same two variants in RPGRIP1L, but not in CC2D2A. Her mother and sister (no proteinuria) harbor the same variant in CC2D2A, but not in RPGRIP1L. These sequencing results strongly suggest that the variants in RPGRIP1L could be pathogenic.
Discussion
RPGRIP1L encodes retinitis pigmentosa GTPase regulator-interacting protein-1 like, a ciliary and retinal protein important in ciliogenesis and tubular function. The mutation of RPGRIP1L is associated with Meckel and Joubert’s syndrome but is not a known FSGS gene. The identified two variants in RPGRIP1L occur in relatively poorly conserved regions. The p.I1005V has been identified in the Genome Aggregation Database (gnomAD) with a minor allele frequency (MAF) 0.00004415 (very rare), while the other variant is not found in gnomAD. The in silico prediction about the effect of the missense mutations from the different algorithms is conflicting. Thus, we plan to use CRISPR/Cas9 to introduce these mutations to establish cell models first to determine their pathogenicity. Our case highlights those mutations in genes not typically thought of as glomerular disease genes may lead to FSGS, most likely as a secondary response.