Deciphering the genetic architecture of retinitis pigmentosa through a combination of panel and whole exome sequencing
Bibliographic record
Abstract
PurposeThe molecular basis of retinitis pigmentosa (RP) is a highly heterogeneous. Many novel pathogenic alleles, genotype-phenotype associations, and disease genes remain to be identified. In this study, we aim to dissect the complex genetic architecture of RP by characterizing a large cohort of RP patients. Methods552 RP patients from different ethnicity groups, including Caucasian and Han Chinese, were recruited. Genomic DNA was extracted from patients’ blood or saliva samples, and sequenced using our custom-designed panel, which includes around 200 retinal disease genes. Patients with negative results from our panel sequencing were further analyzed by whole exome sequencing. ResultsWe successfully identified putatively pathogenic variants in known retinal disease genes for 319 RP cases, achieving a solving rate of approximately 58%. Among the 176 solved simplex cases, multiple inheritance patterns were found, including autosomal recessive (73%), autosomal dominant (14%), x-linked (12%) and even digenic (2%). A total of 460 different pathogenic mutations were identified, 365 of which were novel. Interestingly, 58 mutations were recurrent in multiple solved cases, accounting for approximately 30% of total allele instances. USH2A was the most prevalent causative gene in our cohort, which accounts for about 15% of all the solved case. And EYS is significantly more prevalent (~10 fold) in RP patients from Han Chinese than those from Caucasian population. Surprisingly, around 20% of all the solved cases carried mutations in other retinal disease genes which had not been previously associated with RP. For those cases, where available, clinical reassessments were performed resulting in identification of novel genotype-phenotype correlations and clinical refinements. Finally, whole exome sequencing of unsolved cases revealed multiple candidate disease-causing genes which are currently in the process of further validation. ConclusionsSequencing-based comprehensive genetic testing of large patient cohort yield tremendous amount of new findings at multiple levels of the genetic architecture underlying RP. Information gained from this type of study will lay the foundation toward comprehensive and accurate molecular diagnosis of RP, which is critical for developing proper treatment of the disease.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.003 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| 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".