Identification of a robust DNA methylation signature for Fanconi anemia.
DNA methylation profiling
Fanconi anemia
classifier
diagnostic tool
episignature
gene conversion
hematological disorders
machine learning
mosaicism
variant classification
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 11 2023
02 11 2023
Historique:
received:
29
06
2023
revised:
26
09
2023
accepted:
27
09
2023
pmc-release:
02
05
2024
medline:
6
11
2023
pubmed:
22
10
2023
entrez:
21
10
2023
Statut:
ppublish
Résumé
Fanconi anemia (FA) is a clinically variable and genetically heterogeneous cancer-predisposing disorder representing the most common bone marrow failure syndrome. It is caused by inactivating predominantly biallelic mutations involving >20 genes encoding proteins with roles in the FA/BRCA DNA repair pathway. Molecular diagnosis of FA is challenging due to the wide spectrum of the contributing gene mutations and structural rearrangements. The assessment of chromosomal fragility after exposure to DNA cross-linking agents is generally required to definitively confirm diagnosis. We assessed peripheral blood genome-wide DNA methylation (DNAm) profiles in 25 subjects with molecularly confirmed clinical diagnosis of FA (FANCA complementation group) using Illumina's Infinium EPIC array. We identified 82 differentially methylated CpG sites that allow to distinguish subjects with FA from healthy individuals and subjects with other genetic disorders, defining an FA-specific DNAm signature. The episignature was validated using a second cohort of subjects with FA involving different complementation groups, documenting broader genetic sensitivity and demonstrating its specificity using the EpiSign Knowledge Database. The episignature properly classified DNA samples obtained from bone marrow aspirates, demonstrating robustness. Using the selected probes, we trained a machine-learning model able to classify EPIC DNAm profiles in molecularly unsolved cases. Finally, we show that the generated episignature includes CpG sites that do not undergo functional selective pressure, allowing diagnosis of FA in individuals with reverted phenotype due to gene conversion. These findings provide a tool to accelerate diagnostic testing in FA and broaden the clinical utility of DNAm profiling in the diagnostic setting.
Identifiants
pubmed: 37865086
pii: S0002-9297(23)00352-X
doi: 10.1016/j.ajhg.2023.09.014
pmc: PMC10645556
pii:
doi:
Substances chimiques
Fanconi Anemia Complementation Group Proteins
0
Proteins
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1938-1949Informations de copyright
Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Dr. Sadikovic is a shareholder in EpiSign Inc, a software company involved in commercialization of EpiSign Technology.
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