Dna Methylation Episignatures are Sensitive and Specific Biomarkers for Detection of Patients with Kat6A/Kat6B Variants

Abstract

Accurate diagnosis for patients living with neurodevelopmental disorders is often met with numerous challenges, related to the ambiguity of findings and lack of specificity in genetic variants leading to pathology. Genome-wide DNA methylation analysis has been used to develop highly sensitive and specific ‘episignatures’ as biomarkers capable of differentiating and classifying complex neurodevelopmental disorders. In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene (KAT6A), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B (KAT6B). We demonstrate the ability of our models to differentiate between highly overlapping episignatures, increasing the ability to effectively identify and diagnose these conditions.

Keywords::

• DNA methylation
• epigenetics
• episignature
• KAT6A

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2023-0079

Author Contributions

N Vos, J Reilly: led data analysis and manuscript writing. B Sadikovic: conceived the research, supervised the research project, data analysis and manuscript writing. M Alders: co-supervised the research project and manuscript writing. M Levy, R Relator: assisted data analysis and manuscript writing. M Elting, P Campeau, D Coman, Z Stark, T Yang Tan, D Amor, S Kaur, M StJohn, A Morgan, B Kamien, C Patel, M Tedder, G Merla, P Prontera, M Castori, K Muru, F Collins, J Christodoulou, J Smith, B Ben Zeev, A Murgia, E Leonardi, N Esber, A Martinez-Monseny, D Casas-Alba, M Wallis, M Mannens: recruited patients and participated in research planning and manuscript writing.

Financial & competing interests disclosure

This work was funded by the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval for all human or animal experimental investigations. The study was approved by the Western University Research Ethics Board (REB 106302 and REB 116108). In addition, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was funded by the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.