Deciphering the genetic architecture of retinitis pigmentosa through a combination of panel and whole exome sequencing
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».