Heterozygous Variants in NEK8 Kinase Domain Cause an Autosomal-Dominant Ciliopathy
Bibliographic record
Abstract
Background: NEK8 encodes a protein that localizes to the primary cilium. Biallelic NEK8 variants are known to cause multiorgan developmental defects including renal cystic dysplasia, with heterozygous carrier parents being asymptomatic. This autosomal recessive inheritance is most common for ciliopathies. Complementary to this, we now propose a dominant-negative effect for certain heterozygous NEK8 missense variants in the kinase domain. Methods: We performed genetic testing in patients from several medical centers. To explore the consequences of the identified NEK8 variants we are performing cilia staining assays in patients' skin fibroblast and kidney cells, as well as in mIMCD3 cells overexpressing the identified variants. Results: We identified three distinct heterozygous NEK8 variants in eight families (table 1), all leading to missense alterations in the kinase domain. The large symptomatic family and the de novo occurrences are also in favor of a dominant mode of inheritance. All patients have a kidney phenotype, varying in severity, age of onset and presence of kidney failure. Interestingly the p.Arg45Trp variant is a recurrent variant found in six unrelated families. Our preliminary results from functional studies show normal localization of the NEK8 protein to the Golgi region, but abnormal primary cilia formation, in serum starved patient derived cells - a finding consistent with pathogenicity. Conclusions: We present the first evidence for a pathogenic effect of heterozygous NEK8 variants. Remarkably our patients present with a renal limited phenotype as compared to the multiorgan defects found in patients with biallelic variants. This reveals a new mode of inheritance for NEK8 variants and expands genotype-phenotype correlations for this gene.
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".