DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants
Por:
Vos N, Reilly J, Elting MW, Campeau PM, Coman D, Stark Z, Tan TY, Amor DJ, Kaur S, StJohn M, Morgan AT, Kamien BA, Patel C, Tedder ML, Merla G, Prontera P, Castori M, Muru K, Collins F, Christodoulou J, Smith J, Zeev BB, Murgia A, Leonardi E, Esber N, Martinez-Monseny T, Casas-Alba D, Wallis M, Mannens M, Levy MA, Relator R, Alders M and Sadikovic B
Publicada:
1 may 2023
Ahead of Print:
1 may 2023
Resumen:
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.
Filiaciones:
Vos N:
Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands
Reilly J:
Department of Pathology & Laboratory Medicine, Western University, London, ON, N6A 5C1, Canada
Elting MW:
Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands
Campeau PM:
Department of Pediatrics, Sainte-Justine UHC & University of Montreal, Montreal, QC, H3T 1C5, Canada
Coman D:
Department of Metabolic Medicine, Queensland Children's Hospital, South Brisbane, QLD 4101, Australia
School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia
Stark Z:
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia
Department of Paediatrics, University of Melbourne, Grattan Street, Parkville, Victoria, 3010, Australia
Tan TY:
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia
Department of Paediatrics, University of Melbourne, Grattan Street, Parkville, Victoria, 3010, Australia
Amor DJ:
Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd, Parkville VIC, 3052, Australia
University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, Australia
Kaur S:
Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd, Parkville VIC, 3052, Australia
University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, Australia
StJohn M:
Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd, Parkville VIC, 3052, Australia
University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, Australia
Morgan AT:
Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd, Parkville VIC, 3052, Australia
University of Melbourne Department of Pediatrics, Parkville, Victoria, 3010, Australia
Kamien BA:
Genetics Services of Western Australia, Perth, 6008, Western Australia
Patel C:
Genetic Health Queensland, Royal Brisbane & Women's Hospital, Herston, QLD 4006, Australia
Tedder ML:
Greenwood Genetic Center, Greenwood, SC 29646, United States
Merla G:
Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (Foggia), Italy
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federica II, 5 - 80131, Naples, Italy
Prontera P:
Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Piazza dell'Università, 1, 06123, Perugia PG, Italy
Castori M:
Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (Foggia), Italy
Muru K:
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Riia 23b, 51010, Tartu, Estonia
Collins F:
Discipline of Child and Adolescent Health and Genomic Medicine, Sydney Medical School, Sydney University, Sydney, Camperdown NSW, 2050, Australia
Department of Clinical Genetics, Western Sydney Genetics Program, Children's Hospital at Westmead, Randwick NSW, 2031, Australia
Christodoulou J:
Department of Clinical Genetics, Western Sydney Genetics Program, Children's Hospital at Westmead, Randwick NSW, 2031, Australia
Smith J:
Sydney Children's Hospitals Network-Westmead, Randwick NSW, 2031, Australia
University of Sydney, Camperdown NSW, 2006, Australia
Zeev BB:
Sackler School of Medicine Tel Aviv University, Tel Aviv, 6997801, Israel
Murgia A:
Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Via Giustiniani 3, 35128, Padua, Italy
Leonardi E:
Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Via Giustiniani 3, 35128, Padua, Italy
Esber N:
KAT6A Foundation, 3 Louise Dr., West Nyack, NY 10994, USA
Martinez-Monseny T:
Genetics and Molecular Medicine Department, Rare Disease Pediatric Unit, Hospital Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain
Casas-Alba D:
Genetics and Molecular Medicine Department, Rare Disease Pediatric Unit, Hospital Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain
Wallis M:
Tasmanian Clinical Genetics Service, Tasmanian Health Service, Royal Hobart Hospital, Hobart, TAS 7001, Australia
Mannens M:
Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands
Levy MA:
Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A 5W9, Canada
Relator R:
Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A 5W9, Canada
Alders M:
Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands
Sadikovic B:
Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A 5W9, Canada
Open Access
|