Abstract: PO1270
Rare Variants in Syndromic Ciliopathy Genes as Novel Causes of Isolated Renal Disease in Adults
Session Information
- Cystic Kidney Disease - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Sentell, Zachary T., Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Mougharbel, Lina, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Babayeva, Sima, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Anastasio, Natascia, McGill University Faculty of Medicine and Health Sciences, Montreal, Quebec, Canada
- Chu, Lee lee, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Akpa, Murielle M., Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Goodyer, Paul R., Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Torban, Elena, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Kitzler, Thomas Michael, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
Background
Renal ciliopathies are among the commonest genetic causes of end-stage renal disease (ESRD). Ciliopathies are caused by defects of the primary cilium, an antenna-like organelle with mechanosensory roles, crucial for organ development and maintenance. Disorders of the cilium present early with multi-organ involvement, but some individuals present as adults with organ-specific phenotypes, potentially due to milder mutations and organ-specific effects.
Methods
We identified rare variants in two ciliopathy genes in two unrelated adults presenting with ESRD. ACMG guidelines did not classify these variants as pathogenic, requiring functional validation to establish a causal genotype-phenotype relationship.
Results
Bi-allelic C2CD3 missense variants were identified in a proband with ESRD, suggestive of an isolated renal ciliopathy. C2CD3 is essential for ciliogenesis, with complete loss of cilia in knockout mice (Development 135:4049 2008). Severe mutations were reported in patients with a syndromic ciliopathy (OFD XIV; OMIM# 615948), but no cases of isolated renal disease have been reported. We detected a moderate but consistent shortened cilia length in skin fibroblasts and renal epithelial cells from our proband, suggestive of a milder ciliary defect. Remarkably, the proportion of ciliated cells was significantly reduced in renal epithelial cells but not in fibroblasts, indicating an organ-specific ciliogenesis defect.
Pathogenic variants in CC2D2A cause Joubert and Meckel syndrome, with no isolated renal presentations observed to date (Mol. Genet. Genom. e1603 2021). We identified a novel homozygous nonsense variant (Arg34*) in CC2D2A, classified as not pathogenic due to an alternate start-codon, in a previously healthy 37-year-old male with isolated ESRD of unknown etiology. Using public data (GTEx), we show that protein-coding transcripts harbouring this variant are the predominant trancripts in the kidney when compared to tissues relevant to CC2D2A-related phenotypes (e.g., cerebellum, liver).
Conclusion
Rare variants in known syndromic ciliopathy genes cause isolated renal disease in adults due to potential organ-specifc effects. Using variant classification schemes without functional analysis may not accurately capture the genetic contribution to adult ESRD.
Funding
- Government Support – Non-U.S.