<i>FGF14</i> repeat length and mosaic interruptions: modifiers of spinocerebellar ataxia 27B?
Notice bibliographique
Résumé
Deep intronic FGF14 repeat expansions have been identified as a frequent genetic cause of late-onset cerebellar ataxias, explaining ≤30% of patients. Interruptions between repeats have previously been identified to impact the penetrance in other repeat expansion disorders. Repeat interruptions within FGF14 have yet to be characterized in detail. We used long-range PCR, Sanger sequencing, repeat-primed PCR, Nanopore and PacBio sequencing to distinguish the repeat motifs, mosaicism and number of repeat interruptions present in FGF14-related ataxia patients and unaffected individuals. A total of 304 patients with late-onset ataxia and 190 unaffected individuals were previously screened for repeat expansions in FGF14 by long-range PCR, identifying 37 individuals with expanded repeat lengths (≥250 repeats). These, along with three newly identified expansion carriers were included in the present study, and advanced genetic methods were applied to investigate the repeat composition in 27 patients and 13 unaffected individuals. The expansions, based on Nanopore data, ranged from 236 to 486 repeats (standard deviation = 60), with 20 individuals showing repeat interruptions, including complex motifs such as GAG, GAAGGA, GAAGAAAGAA, GAAAAGAAGAAGGAAGAAGGAA, GAAAAGAAGAAGGAA and GCAGAAGAAGAAGAA. We calculated the longest pure GAA length from the long-read data for all 40 individuals. When comparing the pure GAA tract between patients and unaffected individuals, clusters were apparent based on >200 or <200 repeats. Five ataxia patients with interruptions still had a remaining pure GAA expansion <200. We observed an association of the pure GAA length with age at onset (P = 0.016, R2 = 0.256). Somatically incurred mosaic divergent repeat interruptions were discovered that affect motif length and sequence (mDRILS), which varied in number and mosaicism (frequency: 0.37-0.93). The mDRILS were correlated with pure GAA length (P = 0.022, R2 = 0.334), with a higher mosaic frequency of interruptions in unaffected individuals compared with patients (unaffected: 0.90; patients: 0.67; P = 0.009). We demonstrate that: (i) long-read sequencing is required to detect complex repeat interruptions accurately; (ii) repeat interruptions in FGF14 are mosaic, have various lengths and start positions in the repeat tract, and can thereby be annotated as mDRILS; which (iii) enabled us to establish a categorization based on remaining pure GAA repeats quantifying the impact of mDRILS on pathogenicity or age at onset, dependent on the interruption length and position, with high accuracy; and (iv) we provide evidence that mosaicism stabilizes pure GAA repeats in interrupted FGF14 repeat expansions.
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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 | 0,001 |
| 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 ».