DNA methylation episignature as a novel diagnostic tool for diamond-blackfan anemia
Notice bibliographique
Résumé
Abstract Background Diamond-Blackfan anemia syndrome (DBAS) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by impaired erythropoiesis and significant phenotypic and genetic heterogeneity. Diagnosis can be challenging due to clinical variability and the lack of sensitive and specific biomarkers. Over the past few years, several studies have identified characteristic DNA methylation (DNAm) signatures, or episignatures, associated with various genetic disorders, arising from pathogenic variants impacting epigenetic regulation. In recent years, growing number of episignatures have been utilized as stable and reliable biomarkers for the diagnosis of congenital genetic disorders and for the reclassification of variants of uncertain significance (VUSs), and have been implemented in clinical diagnostic laboratories with significant diagnostic utility in genetically unresolved patients with suspected rare disorders. Purpose and methods In this study, we investigated evidence for a DNA methylation (DNAm) episignature in a cohort of 80 DBAS patients with causative variants in various ribosomal protein genes: DBA1 (RPS19, n=30), DBA4 (RPS17, n=6), DBA5 (RPL35A, n=8), DBA6 (RPL5, n=15), DBA7 (RPL11, n=13), DBA10 (RPS26, n=8). Peripheral blood DNA was extracted using standard techniques. DNAm profiling was performed using the Illumina Infinium Methylation EPIC BeadChip arrays (EPIC v.2) according to the manufacturer's protocol (Illumina, San Diego, CA, USA). Controls were randomly selected from EpiSign Knowledge Database (EKD), at London Health Sciences Centre. Matching of controls and cases for age, sex, and array type was performed using the MatchIt package (version 4.5.1). Results The comparison of DBAS cases with matched controls from the EKD resulted in the identification of a total of 206 differentially methylated probes (DMPs), which enabled the definition of a specific episignature associated with DBAS. Given the clinical overlap between DBAS and Fanconi Anemia (FA), we tested the DBAS episignature in a cohort of FA patients using both supervised and unsupervised clustering approaches. This analysis clearly distinguished FA cases from DBAS cases, highlighting distinct underlying epigenetic differences despite their similar clinical presentations. Furthermore, we developed a specific DNAm classifier for the clinically similar DBA6 and DBA7 subgroups. Additionally, methylation profiles from revertant cases due to uniparental disomy (RPS19:P47L and RPS17 full gene deletion) were consistent with those of non-revertant DBAS cases, with RPS19:P47L showing identical DNAm patterns to non-revertant RPS19:P47L. Applying the DBA episignature analysis to six molecularly uncharacterized cases, three exhibited the DBA pattern. Subsequent genome sequencing identified causative genetic variants in two (RPL5: c.325-380A>G:p.?; RPL26: c.-6+3_-6+25del:p.?), validating the test robustness. Discussion and conclusions This work supports the use of DNA methylation profiling as a valuable diagnostic biomarker in all patients with clinical suspicion of DBAS and critically aiding in the resolution of VUS and molecularly uncharacterized cases. The presence of DBAS episignature in two revertant cases, despite phenotypic correction, indicates that the episignature is a persistent developmental biomarker associated with the underlying genetic mutation, rather than being solely dictated by the current functional status of ribosomal protein production or the severity of the clinical phenotype. Future collaborative efforts via DBA registries are crucial for validating these findings and identifying episignatures for rarer DBA subtypes.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,002 | 0,001 |
| 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) | 0,002 | 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 source (Gemma direct ou Codex distillé), 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 ».