Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Michael A Levy¹, Raissa Relator¹, Haley McConkey¹, Erinija Pranckeviciene¹, Jennifer Kerkhof¹, Mouna Barat-Houari², Sara Bargiacchi³, Elisa Biamino⁴, María Palomares Bralo⁵, Gerarda Cappuccio^{6

7}, Andrea Ciolfi⁸, Angus Clarke⁹, Barbara R DuPont¹⁰, Mariet W Elting¹¹, Laurence Faivre^{12

13}, Timothy Fee¹⁰, Marco Ferilli⁸, Robin S Fletcher¹⁰, Florian Cherick^{14

15}, Aidin Foroutan¹⁶, Michael J Friez¹⁰, Cristina Gervasini¹⁷, Sadegheh Haghshenas¹⁶, Benjamin A Hilton¹⁰, Zandra Jenkins¹⁸, Simranpreet Kaur¹⁹, Suzanne Lewis²⁰, Raymond J Louie¹⁰, Silvia Maitz²¹, Donatella Milani²², Angela T Morgan²³, Renske Oegema²⁴, Elsebet Østergaard^{25

26}, Nathalie R Pallares², Maria Piccione²⁷, Astrid S Plomp¹¹, Cathryn Poulton²⁸, Jack Reilly¹⁶, Rocio Rius^{29

30}, Stephen Robertson¹⁸, Kathleen Rooney^{1

16}, Justine Rousseau³¹, Gijs W E Santen³², Fernando Santos-Simarro⁵, Josephine Schijns³³, Gabriella M Squeo³⁴, Miya St John²³, Christel Thauvin-Robinet^{12

13

35

36}, Giovanna Traficante³, Pleuntje J van der Sluijs³², Samantha A Vergano^{37

38}, Niels Vos¹¹, Kellie K Walden¹⁰, Dimitar Azmanov³⁹, Tugce B Balci^{40

41}, Siddharth Banka^{42

43}, Jozef Gecz^{44

45}, Peter Henneman¹¹, Jennifer A Lee¹⁰, Marcel M A M Mannens¹¹, Tony Roscioli^{46

47

48

49}, Victoria Siu^{40

41}, David J Amor²³, Gareth Baynam^{28

28

50}, Eric G Bend⁵¹, Kym Boycott^{52

53}, Nicola Brunetti-Pierri^{6

7}, Philippe M Campeau³¹, Dominique Campion⁵⁴, John Christodoulou¹⁹, David Dyment^{52

53}, Natacha Esber⁵⁵, Jill A Fahrner⁵⁶, Mark D Fleming⁵⁷, David Genevieve¹⁵, Delphine Heron⁵⁸, Thomas Husson⁵⁹, Kristin D Kernohan^{52

60}, Alisdair McNeill⁶¹, Leonie A Menke³³, Giuseppe Merla^{34

62}, Paolo Prontera⁶³, Cheryl Rockman-Greenberg⁶⁴, Charles Schwartz¹⁰, Steven A Skinner¹⁰, Roger E Stevenson¹⁰, Marie Vincent^{65

66}, Antonio Vitobello^{12

35}, Marco Tartaglia⁸, Marielle Alders¹¹, Matthew L Tedder¹⁰, Bekim Sadikovic^{1

16}

Affiliations

¹ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada.
² Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, CHU Montpellier, Montpellier, France.
³ Medical Genetics Unit, "A. Meyer" Children Hospital of Florence, Florence, Italy.
⁴ Department of Pediatrics, University of Turin, Turin, Italy.
⁵ Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain.
⁶ Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
⁷ Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
⁸ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
⁹ Cardiff University School of Medicine, Cardiff, UK.
¹⁰ Greenwood Genetic Center, Greenwood, South Carolina, USA.
¹¹ Amsterdam UMC, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
¹² INSERM-Université de Bourgogne UMR1231 GAD, Génétique Des Anomalies du Développement, FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France.
¹³ Centre de Référence Maladies Rares, Anomalies du Développement et Syndromes Malformatifs, Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
¹⁴ Genetic Medical Center, CHU Clermont Ferrand, France.
¹⁵ Montpellier University, Reference Center for Rare Disease, Medical Genetic Department for Rare Disease and Personalize Medicine, CHU Montpellier, Montpellier, France.
¹⁶ Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
¹⁷ Division of Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
¹⁸ Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
¹⁹ Brain and Mitochondrial Research Group, Murdoch Children s Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
²⁰ BC Children's and Women's Hospital and Department of Medical Genetics, Faculty of Medicine, University of British Columbia.
²¹ Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, Hospital San Gerardo, Monza, Italy.
²² Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²³ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
²⁴ Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁵ Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
²⁶ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁷ Medical Genetics Unit Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
²⁸ Undiagnosed Diseases Program, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia.
²⁹ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Australia.
³⁰ Department of Paediatrics, University of Melbourne, Melbourne, Australia.
³¹ CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
³² Department of Clinical Genetics, LUMC, Leiden, The Netherlands.
³³ Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
³⁴ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
³⁵ Unité Fonctionnelle d'Innovation Diagnostique des Maladies Rares, FHU-TRANSLAD, France Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon Bourgogne, CHU Dijon Bourgogne, Dijon, France.
³⁶ Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital D'Enfants, CHU Dijon Bourgogne, Dijon, France.
³⁷ Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia, USA.
³⁸ Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia, USA.
³⁹ Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Australia.
⁴⁰ Department of Pediatrics, Division of Medical Genetics, Western University, London, Ontario, Canada.
⁴¹ Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre and Children's Health Research Institute, London, Ontario, Canada.
⁴² Division of Evolution, Infection & Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
⁴³ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom.
⁴⁴ School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, Australia.
⁴⁵ South Australian Health and Medical Research Institute, Adelaide, Australia.
⁴⁶ Neuroscience Research Australia (NeuRA), Sydney, Australia.
⁴⁷ Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁴⁸ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, Australia.
⁴⁹ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia.
⁵⁰ Division of Paediatrics and Telethon Kids Institute, Faculty of Health and Medical Sciences, Perth, Australia.
⁵¹ PreventionGenetics, Marshfield, Wisconsin, USA.
⁵² Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
⁵³ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
⁵⁴ INSERM U1245, Faculté de Médecine, Rouen, France.
⁵⁵ KAT6A Foundation, New York, New York, USA.
⁵⁶ Departments of Genetic Medicine and Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA.
⁵⁷ Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵⁸ AP-HP, Département de Génétique Médicale, Groupe Hospitalier Pitié Salpétrière, Paris, France.
⁵⁹ Department of Genetics and Reference Center for Developmental Disorders, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.
⁶⁰ Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁶¹ Department of Neuroscience, University of Sheffield, UK, and Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
⁶² Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
⁶³ Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Perugia, Italy.
⁶⁴ Department of Pediatrics and Child Health, Rady Faculty of Health Sciences, University of Manitoba and Program in Genetics and Metabolism, Shared Health MB, Winnipeg, Manitoba, Canada.
⁶⁵ Service de génétique Médicale, CHU Nantes, Nantes, France.
⁶⁶ Institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.

PMID: 35904121
DOI: 10.1002/humu.24446

Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Michael A Levy et al. Hum Mutat. 2022 Nov.

. 2022 Nov;43(11):1609-1628.

doi: 10.1002/humu.24446. Epub 2022 Aug 21.

Authors

Affiliations

¹ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada.
² Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, CHU Montpellier, Montpellier, France.
³ Medical Genetics Unit, "A. Meyer" Children Hospital of Florence, Florence, Italy.
⁴ Department of Pediatrics, University of Turin, Turin, Italy.
⁵ Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain.
⁶ Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
⁷ Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
⁸ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
⁹ Cardiff University School of Medicine, Cardiff, UK.
¹⁰ Greenwood Genetic Center, Greenwood, South Carolina, USA.
¹¹ Amsterdam UMC, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
¹² INSERM-Université de Bourgogne UMR1231 GAD, Génétique Des Anomalies du Développement, FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France.
¹³ Centre de Référence Maladies Rares, Anomalies du Développement et Syndromes Malformatifs, Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
¹⁴ Genetic Medical Center, CHU Clermont Ferrand, France.
¹⁵ Montpellier University, Reference Center for Rare Disease, Medical Genetic Department for Rare Disease and Personalize Medicine, CHU Montpellier, Montpellier, France.
¹⁶ Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
¹⁷ Division of Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
¹⁸ Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
¹⁹ Brain and Mitochondrial Research Group, Murdoch Children s Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
²⁰ BC Children's and Women's Hospital and Department of Medical Genetics, Faculty of Medicine, University of British Columbia.
²¹ Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, Hospital San Gerardo, Monza, Italy.
²² Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²³ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia.
²⁴ Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁵ Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
²⁶ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁷ Medical Genetics Unit Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
²⁸ Undiagnosed Diseases Program, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia.
²⁹ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Australia.
³⁰ Department of Paediatrics, University of Melbourne, Melbourne, Australia.
³¹ CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
³² Department of Clinical Genetics, LUMC, Leiden, The Netherlands.
³³ Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
³⁴ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
³⁵ Unité Fonctionnelle d'Innovation Diagnostique des Maladies Rares, FHU-TRANSLAD, France Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon Bourgogne, CHU Dijon Bourgogne, Dijon, France.
³⁶ Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital D'Enfants, CHU Dijon Bourgogne, Dijon, France.
³⁷ Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia, USA.
³⁸ Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia, USA.
³⁹ Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Australia.
⁴⁰ Department of Pediatrics, Division of Medical Genetics, Western University, London, Ontario, Canada.
⁴¹ Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre and Children's Health Research Institute, London, Ontario, Canada.
⁴² Division of Evolution, Infection & Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
⁴³ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom.
⁴⁴ School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, Australia.
⁴⁵ South Australian Health and Medical Research Institute, Adelaide, Australia.
⁴⁶ Neuroscience Research Australia (NeuRA), Sydney, Australia.
⁴⁷ Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
⁴⁸ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, Australia.
⁴⁹ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia.
⁵⁰ Division of Paediatrics and Telethon Kids Institute, Faculty of Health and Medical Sciences, Perth, Australia.
⁵¹ PreventionGenetics, Marshfield, Wisconsin, USA.
⁵² Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
⁵³ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
⁵⁴ INSERM U1245, Faculté de Médecine, Rouen, France.
⁵⁵ KAT6A Foundation, New York, New York, USA.
⁵⁶ Departments of Genetic Medicine and Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA.
⁵⁷ Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵⁸ AP-HP, Département de Génétique Médicale, Groupe Hospitalier Pitié Salpétrière, Paris, France.
⁵⁹ Department of Genetics and Reference Center for Developmental Disorders, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.
⁶⁰ Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁶¹ Department of Neuroscience, University of Sheffield, UK, and Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
⁶² Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
⁶³ Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Perugia, Italy.
⁶⁴ Department of Pediatrics and Child Health, Rady Faculty of Health Sciences, University of Manitoba and Program in Genetics and Metabolism, Shared Health MB, Winnipeg, Manitoba, Canada.
⁶⁵ Service de génétique Médicale, CHU Nantes, Nantes, France.
⁶⁶ Institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.

PMID: 35904121
DOI: 10.1002/humu.24446

Abstract

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.

Keywords: DNA methylation; clinical diagnostics; episignatures; neurodevelopmental syndromes.

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Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Affiliations

Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Authors

Affiliations

Abstract

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REFERENCES

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