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

doi:10.2217/epi-2023-0079

. 2023 Mar;15(6):351-367.

doi: 10.2217/epi-2023-0079. Epub 2023 May 30.

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

Niels Vos¹, Jack Reilly², Mariet W Elting¹, Philippe M Campeau³, David Coman^{4

5}, Zornitza Stark^{6

7}, Tiong Yang Tan^{6

7}, David J Amor^{8

9}, Simran Kaur^{8

9}, Miya StJohn^{8

9}, Angela T Morgan^{8

9}, Benjamin A Kamien¹⁰, Chirag Patel¹¹, Matthew L Tedder¹², Giuseppe Merla^{13

14}, Paolo Prontera¹⁵, Marco Castori¹⁶, Kai Muru¹⁷, Felicity Collins^{18

19}, John Christodoulou¹⁹, Janine Smith^{20

21}, Bruria Ben Zeev²², Alessandra Murgia²³, Emanuela Leonardi²³, Natacha Esber²⁴, Antonio Martinez-Monseny²⁵, Didac Casas-Alba²⁵, Matthew Wallis²⁶, Marcel Mannens¹, Michael A Levy²⁷, Raissa Relator²⁷, Marielle Alders¹, Bekim Sadikovic²⁷

Affiliations

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.

PMID: 37249002
DOI: 10.2217/epi-2023-0079

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

Niels Vos et al. Epigenomics. 2023 Mar.

. 2023 Mar;15(6):351-367.

doi: 10.2217/epi-2023-0079. Epub 2023 May 30.

Authors

Affiliations

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.

PMID: 37249002
DOI: 10.2217/epi-2023-0079

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; KAT6A; epigenetics; episignature.

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

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

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