TY - JOUR
T1 - Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders
AU - Levy, Michael A
AU - McConkey, Haley
AU - Kerkhof, Jennifer
AU - Barat-Houari, Mouna
AU - Bargiacchi, Sara
AU - Biamino, Elisa
AU - Bralo, María Palomares
AU - Cappuccio, Gerarda
AU - Ciolfi, Andrea
AU - Clarke, Angus
AU - DuPont, Barbara R
AU - Elting, Mariet W
AU - Faivre, Laurence
AU - Fee, Timothy
AU - Fletcher, Robin S
AU - Cherik, Florian
AU - Foroutan, Aidin
AU - Friez, Michael J
AU - Gervasini, Cristina
AU - Haghshenas, Sadegheh
AU - Hilton, Benjamin A
AU - Jenkins, Zandra
AU - Kaur, Simranpreet
AU - Lewis, Suzanne
AU - Louie, Raymond J
AU - Maitz, Silvia
AU - Milani, Donatella
AU - Morgan, Angela T
AU - Oegema, Renske
AU - Østergaard, Elsebet
AU - Pallares, Nathalie Ruiz
AU - Piccione, Maria
AU - Pizzi, Simone
AU - Plomp, Astrid S
AU - Poulton, Cathryn
AU - Reilly, Jack
AU - Relator, Raissa
AU - Rius, Rocio
AU - Robertson, Stephen
AU - Rooney, Kathleen
AU - Rousseau, Justine
AU - Santen, Gijs W E
AU - Santos-Simarro, Fernando
AU - Schijns, Josephine
AU - Squeo, Gabriella Maria
AU - St John, Miya
AU - Thauvin-Robinet, Christel
AU - Traficante, Giovanna
AU - van der Sluijs, Pleuntje J
AU - Vergano, Samantha A
N1 - Funding Information:
Funding for this study is provided in part by the London Health Sciences Molecular Diagnostics Development Fund and the Genome Canada Genomic Applications Partnership Program. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children's Hospital Foundation . Funding was provided by the Italian Ministry of Health (Ricerca Corrente to A.C.; 5x1000 , CCR-2017-23669081 , and RCR-2020-23670068_001 to M.T.) and the Italian Ministry of Research ( FOE 2019 to M.T.). The authors wish to acknowledge Care4Rare for providing some of the patient samples. Support for this study is provided in part by the MKHK Association.
Publisher Copyright:
© 2021 The Author(s)
PY - 2022/1/13
Y1 - 2022/1/13
N2 - Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.
AB - Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.
KW - Clinical diagnostics
KW - DNA methylation
KW - Epigenetics
KW - Episignatures
KW - Neurodevelopmental disorders
UR - http://www.scopus.com/inward/record.url?scp=85128406827&partnerID=8YFLogxK
U2 - 10.1016/j.xhgg.2021.100075
DO - 10.1016/j.xhgg.2021.100075
M3 - Article
C2 - 35047860
SN - 2666-2477
VL - 3
SP - 1
EP - 18
JO - HGG advances
JF - HGG advances
IS - 1
M1 - 100075
ER -