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RESEARCH PRODUCT
Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders
Julien Van-gilsKyoko TakanoVictor P. PedroLauren BrickPascale Saugier-veberTugce B. BalciAntonio VitobelloMarielle AldersJustine RousseauFrédéric LaumonnierChristel Thauvin-robinetRaoul C.m. HennekamTjitske KleefstraMatt TedderJennifer KerkhofDamien SanlavilleGaël NicolasFrançois LecoquierreDelphine HéronHanxin LinSophie RondeauMariya KozenkoSimone PizziAlexandra AfenjarVictoria Mok SiuChristèle DubourgDavid GenevièveErfan Aref-eshghiSolveig HeideBarbara R. DupontPeter AinsworthDavid I. RodenhiserBoris KerenNicole De LeeuwSandra WhalenMartine RaynaudDamien UlvelingNathalie Ruiz-pallaresValérie Cormier-daireMouna Barat-houariMichael A. LevyRoger E. StevensonJennifer A. LeeSteven A. SkinnerAlan Graham StuartLaurence FaivreMarie ShawGaetan LescaPeter HennemanThierry BienvenuMarco TartagliaCharles E. SchwartzAndrea CiolfiMichael J. FriezMichael FieldMike KadourGuillaume VelascoJozef GeczClaire FrancastelDidier LacombePhilippe M. CampeauJean-christophe AndrauBekim SadikovicBekim SadikovicMarcel M.a.m. MannensJennifer MastersCyril MignotPatricia FergelotNicolas Chatronsubject
0301 basic medicine[SDV]Life Sciences [q-bio]Computational biology030105 genetics & heredityBiologyPediatricsArticleCohort Studiesmolecular diagnostics03 medical and health sciencessymbols.namesakeGenetic HeterogeneityGene duplicationGeneticsHumansHunter-McAlpine syndromeGenetics (clinical)Mass screening030304 developmental biologyEpiSignGenetics0303 health sciencesNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]DNA methylationGenetic heterogeneity030305 genetics & heredityCorrectionSyndromeDNA MethylationMolecular diagnosticsPhenotypePenetranceHuman genetics3. Good healthepisignaturegenomic DNA030104 developmental biologyPhenotypeNeurodevelopmental DisordersDNA methylationuncertain clinical casesMendelian inheritancesymbolsIdentification (biology)VUS classificationdescription
Contains fulltext : 218274.pdf (Publisher’s version ) (Closed access) Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-03-05 |