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Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Authors :
Aref-Eshghi E
Kerkhof J
Pedro VP
Barat-Houari M
Ruiz-Pallares N
Andrau JC
Lacombe D
Van-Gils J
Fergelot P
Dubourg C
Cormier-Daire V
Rondeau S
Lecoquierre F
Saugier-Veber P
Nicolas G
Lesca G
Chatron N
Sanlaville D
Vitobello A
Faivre L
Thauvin-Robinet C
Laumonnier F
Raynaud M
Alders M
Mannens M
Henneman P
Hennekam RC
Velasco G
Francastel C
Ulveling D
Ciolfi A
Pizzi S
Tartaglia M
Heide S
Héron D
Mignot C
Keren B
Whalen S
Afenjar A
Bienvenu T
Campeau PM
Rousseau J
Levy MA
Brick L
Kozenko M
Balci TB
Siu VM
Stuart A
Kadour M
Masters J
Takano K
Kleefstra T
de Leeuw N
Field M
Shaw M
Gecz J
Ainsworth PJ
Lin H
Rodenhiser DI
Friez MJ
Tedder M
Lee JA
DuPont BR
Stevenson RE
Skinner SA
Schwartz CE
Genevieve D
Sadikovic B
Source :
American journal of human genetics [Am J Hum Genet] 2020 Mar 05; Vol. 106 (3), pp. 356-370. Date of Electronic Publication: 2020 Feb 27.
Publication Year :
2020

Abstract

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.<br /> (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1537-6605
Volume :
106
Issue :
3
Database :
MEDLINE
Journal :
American journal of human genetics
Publication Type :
Academic Journal
Accession number :
32109418
Full Text :
https://doi.org/10.1016/j.ajhg.2020.01.019