Mutation of beta-tubulin 4B gene ( <i>TUBB4B)</i> causes autosomal dominant retinitis pigmentosa with sensorineural hearing loss in a multigenerational family
Bibliographic record
Abstract
Purpose Members of a multigenerational Canadian family presented to an inherited retinal degeneration (IRD) clinic with retinitis pigmentosa (RP) and sensorineural hearing loss, reminiscent of an Usher syndrome phenotype. Biallelic disease-causing variants in the known Usher syndrome genes were not identified. Therefore, we enrolled further family members in this study and examined whether other IRD gene variants could explain the phenotype in the family. Methods Family members underwent a comprehensive ophthalmic examination, including best-corrected visual acuity, direct and indirect ophthalmoscopy, fundus photography, visual field testing, spectral-domain optical coherence tomography, audiological examination, and genetic testing. Some patients also had autofluorescence imaging. Loss-of-function testing was initiated by antisense morpholino knockdown of tubb4b in zebrafish. Results Multimodal clinical testing in affected patients revealed an autosomal dominant late-onset presentation of RP associated with progressive, bilateral sensorineural hearing loss that occurred in the second to third decades of life with no vestibular involvement. Panel-based genetic testing revealed a heterozygous c.1168C>T, p.Arg390Trp variant in the beta-tubulin 4B gene (TUBB4B) only in affected family members. Based on in silico analysis, segregation analysis through the family, and literature evaluation, this variant is likely to be the disease-causing variant inherited in an autosomal dominant manner. We searched our local database of ~1,000 patients with IRD, and no other TUBB4B variants were identified, confirming this is a rare disease variant. Knockdown of tubb4b in zebrafish revealed cone and rod photoreceptor abnormalities in the retina and hydrocephalus in the developing brain, resulting in early larval lethality. Conclusions For the first time, we describe a multigenerational family with a TUBB4B gene variant p.(Arg390Trp) segregating with deaf-blindness, establishing autosomal dominant inheritance. This further confirms that the Arg390 codon is a mutation hotspot. We also expand the range of phenotypes seen with the p.(Arg390Trp) TUBB4B gene variant to include typical RP as well as a milder, pericentral RP. Furthermore, our studies suggest there is conservation of TUBB4B ciliary function between zebrafish and humans, making zebrafish a better model system for studying vision loss than the mouse model.
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.003 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".