Rare Variants in Syndromic Ciliopathy Genes as Novel Causes of Isolated Renal Disease in Adults
Bibliographic record
Abstract
Background: Renal ciliopathies are among the commonest genetic causes of endstage 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). Conclusions: 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".