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Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders
- Source :
- American journal of human genetics, 106(3), 356-370. Cell Press, American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2020, 106 (3), pp.356-370. ⟨10.1016/j.ajhg.2020.01.019⟩, American Journal of Human Genetics, 2020, 106 (3), pp.356-370. ⟨10.1016/j.ajhg.2020.01.019⟩, Am J Hum Genet, Paediatrics Publications, American Journal of Human Genetics, 106, 3, pp. 356-370, American Journal of Human Genetics, 106, 356-370
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
[SDV]Life Sciences [q-bio]
Computational biology
030105 genetics & heredity
Biology
Pediatrics
Article
Cohort Studies
molecular diagnostics
03 medical and health sciences
symbols.namesake
Genetic Heterogeneity
Gene duplication
Genetics
Humans
Hunter-McAlpine syndrome
Genetics (clinical)
Mass screening
030304 developmental biology
EpiSign
0303 health sciences
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
DNA methylation
Genetic heterogeneity
030305 genetics & heredity
Correction
Syndrome
DNA Methylation
Molecular diagnostics
Phenotype
Penetrance
Human genetics
3. Good health
episignature
genomic DNA
030104 developmental biology
Neurodevelopmental Disorders
uncertain clinical cases
Mendelian inheritance
symbols
Identification (biology)
VUS classification
Subjects
Details
- Language :
- English
- ISSN :
- 00029297 and 15376605
- Database :
- OpenAIRE
- Journal :
- American journal of human genetics, 106(3), 356-370. Cell Press, American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2020, 106 (3), pp.356-370. ⟨10.1016/j.ajhg.2020.01.019⟩, American Journal of Human Genetics, 2020, 106 (3), pp.356-370. ⟨10.1016/j.ajhg.2020.01.019⟩, Am J Hum Genet, Paediatrics Publications, American Journal of Human Genetics, 106, 3, pp. 356-370, American Journal of Human Genetics, 106, 356-370
- Accession number :
- edsair.doi.dedup.....bd1d24b3fed514c0a55ce16403898b8f