@article{66fbeaeabf4d4a05a093159514e4c1ca,
title = "Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations",
abstract = "The term “recurrent constellations of embryonic malformations” (RCEM) is used to describe a number of multiple malformation associations that affect three or more body structures. The causes of these disorders are currently unknown, and no diagnostic marker has been identified. Consequently, providing a definitive diagnosis in suspected individuals is challenging. In this study, genome-wide DNA methylation analysis was conducted on DNA samples obtained from the peripheral blood of 53 individuals with RCEM characterized by clinical features recognized as VACTERL and/or oculoauriculovertebral spectrum association. We identified a common DNA methylation episignature in 40 out of the 53 individuals. Subsequently, a sensitive and specific binary classifier was developed based on the DNA methylation episignature. This classifier can facilitate the use of RCEM episignature as a diagnostic biomarker in a clinical setting. The study also investigated the functional correlation of RCEM DNA methylation relative to other genetic disorders with known episignatures, highlighting the common genomic regulatory pathways involved in the pathophysiology of RCEM.",
keywords = "DNA methylation, epigenetics, episignature, OAV, recurrent constellations of embryonic malformations, VACTERL",
author = "Sadegheh Haghshenas and Karim Karimi and Stevenson, {Roger E.} and Levy, {Michael A.} and Raissa Relator and Jennifer Kerkhof and Jessica Rzasa and Haley McConkey and Carolyn Lauzon-Young and Balci, {Tugce B.} and White-Brown, {Alexandre M.} and Carter, {Melissa T.} and Julie Richer and Armour, {Christine M.} and Sawyer, {Sarah L.} and Bhola, {Priya T.} and Tedder, {Matthew L.} and Skinner, {Cindy D.} and {van Rooij}, {Iris A.L.M.} and {van de Putte}, Romy and {de Blaauw}, Ivo and Koeck, {Rebekka M.} and Alexander Hoischen and Han Brunner and Esteki, {Masoud Zamani} and Anna Pelet and Stanislas Lyonnet and Jeanne Amiel and Boycott, {Kym M.} and Bekim Sadikovic",
note = "Funding Information: This work was funded in part by the government of Canada through Genome Canada and the Ontario Genomics Institute ( OGI-188 ) awarded to B.S., the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute ( OGI-147 ), the Canadian Institutes of Health Research ( CIHR GP1-155867 ), Ontario Research Foundation , Genome Alberta , Genome British Columbia , G\u00E9nome Qu\u00E9bec , and Children's Hospital of Eastern Ontario Foundation to K.M.B., and Greenwood Genetic Center Foundation to R.E.S. A.H. and H.B. were supported by the Solve-RD project . The Solve-RD project received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 779257 . J.A.\u2019s work is funded by MSDAVENIR (Devo-Decode project) and Mutuelles AXA (Chaire T\u00EAte et C\u0153ur). The authors would like to thank Prof. Dr. Christoph Bock, CeMM and BSF, Vienna for his technical assistance. Funding Information: This work was funded in part by the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188) awarded to B.S. the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research (CIHR GP1-155867), Ontario Research Fund, Genome Alberta, Genome British Columbia, G\u00E9nome Qu\u00E9bec, and Children's Hospital of Eastern Ontario Foundation to K.M.B. and Greenwood Genetic Center Foundation to R.E.S. A.H. and H.B. were supported by the Solve-RD project. The Solve-RD project received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 779257. J.A.\u2019s work is funded by MSDAVENIR (Devo-Decode project) and Mutuelles AXA (Chaire T\u00EAte et C\u0153ur). The authors would like to thank Prof. Dr. Christoph Bock, CeMM and BSF, Vienna for his technical assistance. Conceptualization: S.H. K.K. K.M.B. and B.S.; data curation: S.H. K.K. J.K. and J.R.; formal analysis: S.H. K.K. M.A.L. and R.R.; investigation: S.H. K.K. M.A.L. R.R. J.K. and J.R.; sample collection: R.E.S. A.M.W.-B, M.T.C. J.R. C.M.A. S.L.S. P.T.B. M.L.T. C.D.S. I.A.L.M.v.R. R.v.d.P. I.d.B. R.M.K. A.H. H.B. M.Z.E. A.P. J.A. S.L. T.B.B. and K.M.B.; methodology: S.H. K.K. M.A.L. and R.R.; project administration: B.S. K.M.B. H.M. and C.L.-Y.; software: S.H. K.K. M.A.L. and R.R.; writing \u2013 original draft: S.H. K.K. R.E.S. K.M.B. and B.S.; writing \u2013 review and editing: all authors. B.S. is a shareholder in EpiSign Inc. involved in commercial uses of EpiSign technology. Publisher Copyright: {\textcopyright} 2024 American Society of Human Genetics",
year = "2024",
month = aug,
day = "8",
doi = "10.1016/j.ajhg.2024.07.005",
language = "English",
volume = "111",
pages = "1643--1655",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "8",
}