DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants

Author:

Vos Niels1,Reilly Jack2ORCID,Elting Mariet W1,Campeau Philippe M3,Coman David45,Stark Zornitza67,Tan Tiong Yang67,Amor David J89,Kaur Simran89,StJohn Miya89,Morgan Angela T89,Kamien Benjamin A10,Patel Chirag11,Tedder Matthew L12,Merla Giuseppe1314,Prontera Paolo15,Castori Marco16,Muru Kai17,Collins Felicity1819,Christodoulou John19,Smith Janine2021,Zeev Bruria Ben22,Murgia Alessandra23,Leonardi Emanuela23,Esber Natacha24,Martinez-Monseny Antonio25,Casas-Alba Didac25,Wallis Matthew26,Mannens Marcel1ORCID,Levy Michael A27,Relator Raissa27,Alders Marielle1,Sadikovic Bekim27ORCID

Affiliation:

1. Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands

2. Department of Pathology & Laboratory Medicine, Western University, London, ON, N6A 5C1, Canada

3. Department of Pediatrics, Sainte-Justine UHC & University of Montreal, Montreal, QC, H3T 1C5, Canada

4. Department of Metabolic Medicine, Queensland Children’s Hospital, South Brisbane, QLD 4101, Australia

5. School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia

6. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, Victoria, 3052, Australia

7. Department of Paediatrics, University of Melbourne, Grattan Street, Parkville, Victoria, 3010, Australia

8. Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Rd, Parkville VIC, 3052, Australia

9. University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, Australia

10. Genetics Services of Western Australia, Perth, 6008, Western Australia

11. Genetic Health Queensland, Royal Brisbane & Women’s Hospital, Herston, QLD 4006, Australia

12. Greenwood Genetic Center, Greenwood, SC 29646, United States

13. Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (Foggia), Italy

14. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federica II, 5 - 80131, Naples, Italy

15. Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Piazza dell'Università, 1, 06123, Perugia PG, Italy

16. Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (Foggia), Italy

17. Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Riia 23b, 51010, Tartu, Estonia

18. Discipline of Child and Adolescent Health and Genomic Medicine, Sydney Medical School, Sydney University, Sydney, Camperdown NSW, 2050, Australia

19. Department of Clinical Genetics, Western Sydney Genetics Program, Children's Hospital at Westmead, Randwick NSW, 2031, Australia

20. Sydney Children's Hospitals Network-Westmead, Randwick NSW, 2031, Australia

21. University of Sydney, Camperdown NSW, 2006, Australia.

22. Sackler School of Medicine Tel Aviv University, Tel Aviv, 6997801, Israel

23. Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Via Giustiniani 3, 35128, Padua, Italy

24. KAT6A Foundation, 3 Louise Dr., West Nyack, NY 10994, USA

25. Genetics and Molecular Medicine Department, Rare Disease Pediatric Unit, Hospital Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain

26. Tasmanian Clinical Genetics Service, Tasmanian Health Service, Royal Hobart Hospital, Hobart, TAS 7001, Australia

27. Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A 5W9, Canada

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.

Funder

Ontario Genomics Institute

Publisher

Future Medicine Ltd

Subject

Cancer Research,Genetics

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