Expansion of the <i>ABCA4</i>-Associated Retinopathy Spectrum: Severe Variants Can be Associated With Early-Onset Severe Retinal Dystrophy
Bibliographic record
Abstract
Purpose: Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are inherited retinal diseases that are characterized by severe visual loss very early in life. Whereas LCA is characterized by loss of vision in the first year of life, nystagmus, and absent or abnormal electrical signals on electroretinogram, persons with EOSRD show onset of disease between 1 and 5 years of age, with better preserved visual acuity and some signals on an electroretinogram. We investigated the genetic cause of disease and clinical characteristics in three probands with EOSRD. Methods: All patients were examined by at least two ophthalmologists to reach a clinical diagnosis. APEX microarray screening, smMIP-based sequencing, and whole exome and whole genome sequencing were used to obtain a genetic diagnosis and investigate potential modifiers. Results: The EOSRD phenotype of these three probands was established through ophthalmological investigation. Biallelic severe ABCA4 variants were identified after the phenotypic diagnosis of EOSRD in these probands. We then asked whether additional gene defects may be involved and worsen the phenotype. Through whole genome sequencing we identified two NBAS variants in patient 1 and a well-known homozygous, hypomorphic missense variant in CNGB3 in patient 3. Conclusions: We propose that biallelic severe ABCA4 variants can be implicated in EOSRD. We hypothesize that the ABCA4 and CNGB3 variants could have an additive effect given the colocalization of the encoded proteins in cone photoreceptors cell membranes. Whether the CNGB3 and NBAS variants play a modifying role remains to be investigated.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.001 | 0.004 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".