Use of patient-derived cell models for characterization of compound heterozygous hypomorphic <i>C2CD3</i> variants in a patient with isolated nephronophthisis
Bibliographic record
Abstract
BACKGROUND: Primary ciliopathies are a heterogeneous group of rare disorders predominantly caused by autosomal-recessive genetic variants that disrupt non-motile ciliary function. They often manifest as a syndromic phenotype, frequently involving the kidney. Biallelic pathogenic variants in C2CD3 disrupt ciliogenesis and Sonic Hedgehog (SHH) signaling, resulting in a severe ciliopathy (Orofaciodigital syndrome XIV, OMIM 615948). We present compound heterozygous missense variants in C2CD3 that partially disrupt ciliary function in a patient with isolated renal disease. METHODS: Exome sequencing identified biallelic C2CD3 missense variants (p.Pro168Leu; p.Thr2079Met). Patient-derived fibroblasts and urinary renal epithelial cells (URECs), and human RPE-1 C2CD3 knockout (KO) cell-lines were used for in vitro studies. RESULTS: Cilia length was significantly shorter in patient-derived fibroblasts compared to an unaffected sibling (2.309 vs. 2.850 μm, P < 0.0001), while URECs showed significantly shortened cilia (2.068 vs. 2.807 μm, P < 0.0001) and a 40.8% reduction in ciliation (P < 0.001). The latter was not observed in fibroblasts, suggesting a kidney-specific effect. SHH signaling was dysregulated in patient cells as expression of GLI3 activator protein and GLI1 mRNA was significantly reduced. C2CD3 localization to the basal body was significantly reduced in patient URECs. Finally, rescue experiments in C2CD3 KO RPE-1 cells corroborated these findings by demonstrating a reduced capacity to restore ciliogenesis for each variant. CONCLUSION: Biallelic hypomorphic missense variants in C2CD3 may contribute to an isolated nephronophthisis phenotype with impaired ciliogenesis and SHH signaling. Our findings underscore the importance of functional testing to characterize candidate gene-disease relationships in patients with nephropathy of unknown etiology.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".