Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations

Sadegheh Haghshenas; Karim Karimi; Roger E Stevenson; Michael A Levy; Raissa Relator; Jennifer Kerkhof; Jessica Rzasa; Haley McConkey; Carolyn Lauzon-Young; Tugce B Balci; Alexandre M White-Brown; Melissa T Carter; Julie Richer; Christine M Armour; Sarah L Sawyer; Priya T Bhola; Matthew L Tedder; Cindy D Skinner; Iris A L M van Rooij; Romy van de Putte; Ivo de Blaauw; Rebekka M Koeck; Alexander Hoischen; Han Brunner; Masoud Zamani Esteki; Anna Pelet; Stanislas Lyonnet; Jeanne Amiel; Kym M Boycott; Bekim Sadikovic

doi:10.1016/j.ajhg.2024.07.005

Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations

Am J Hum Genet. 2024 Aug 8;111(8):1643-1655. doi: 10.1016/j.ajhg.2024.07.005. Epub 2024 Jul 31.

Authors

Sadegheh Haghshenas¹, Karim Karimi¹, Roger E Stevenson², Michael A Levy¹, Raissa Relator¹, Jennifer Kerkhof¹, Jessica Rzasa¹, Haley McConkey³, Carolyn Lauzon-Young³, Tugce B Balci⁴, Alexandre M White-Brown⁵, Melissa T Carter⁶, Julie Richer⁶, Christine M Armour⁶, Sarah L Sawyer⁶, Priya T Bhola⁶, Matthew L Tedder², Cindy D Skinner², Iris A L M van Rooij⁷, Romy van de Putte⁷, Ivo de Blaauw⁸, Rebekka M Koeck⁹, Alexander Hoischen¹⁰, Han Brunner¹¹, Masoud Zamani Esteki⁹, Anna Pelet¹², Stanislas Lyonnet¹³, Jeanne Amiel¹³, Kym M Boycott¹⁴, Bekim Sadikovic¹⁵

Affiliations

¹ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
² Greenwood Genetic Center, Greenwood, SC 29646, USA.
³ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
⁴ Department of Pediatrics, Division of Medical Genetics, Western University, London, ON, Canada; Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre and Children's Health Research Institute, London, ON, Canada.
⁵ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
⁶ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁷ Department IQ Health, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands.
⁸ Department of Surgery-Pediatric Surgery, Radboudumc Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
⁹ Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, the Netherlands; Department of Genetics and Cell Biology, GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands.
¹⁰ Department of Human Genetics and Donders Center for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands; Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
¹¹ Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, the Netherlands; Department of Genetics and Cell Biology, GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands; Department of Human Genetics and Donders Center for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
¹² Laboratory of Embryology and Genetics of Human Malformations, Institut National de La Santé et de La Recherche Médicale (INSERM) UMR 1163, Institut Imagine and Université Paris Cité, Paris, France.
¹³ Laboratory of Embryology and Genetics of Human Malformations, Institut National de La Santé et de La Recherche Médicale (INSERM) UMR 1163, Institut Imagine and Université Paris Cité, Paris, France; Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
¹⁴ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. Electronic address: [email protected].
¹⁵ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada. Electronic address: [email protected].

PMID: 39089258
PMCID: PMC11339616 (available on 2025-02-08)
DOI: 10.1016/j.ajhg.2024.07.005

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; OAV; VACTERL; epigenetics; episignature; recurrent constellations of embryonic malformations.

MeSH terms

Abnormalities, Multiple / genetics
DNA Methylation*
Female
Humans
Limb Deformities, Congenital / diagnosis
Limb Deformities, Congenital / genetics
Male