Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder

Marissa J Maroni^{1

2

3}, Melissa Barton^{2

3

4}, Katherine Lynch^{2

3}, Ashish R Deshwar^{5

6

7

8

9}, Philip D Campbell^{10

11}, Josephine Millard^{2

11}, Rachel Lee¹², Annastelle Cohen^{2

3

4}, Rili Ahmad^{2

3}, Alekh Paranjapye^{2

3}, Víctor Faundes¹³, Gabriela M Repetto¹⁴, Caoimhe McKenna¹⁵, Amelle L Shillington¹⁶, Chanika Phornphutkul¹⁷, Hanne B Hove¹⁸, Grazia M S Mancini¹⁹, Rachel Schot^{19

20}, Tahsin Stefan Barakat^{19

20

21}, Christopher M Richmond^{22

23}, Julie Lauzon²⁴, Ahmed Ibrahim Elsayed Ibrahim²⁵, Caroline Nava^{26

27}, Delphine Héron²⁷, Minke M A van Aalst¹⁹, Slavena Atemin²⁸, Mila Sleptsova^{28

29}, Iliyana Aleksandrova³⁰, Albena Todorova^{28

29}, Debra L Watkins³¹, Mariya A Kozenko³¹, Daniel Natera-de Benito³², Carlos Ortez³², Berta Estevez-Arias^{32

33}, François Lecoquierre³⁴, Kévin Cassinari³⁴, Anne-Marie Guerrot³⁴, Jonathan Levy^{35

36}, Xenia Latypova^{35

36}, Alain Verloes^{35

36}, A Micheil Innes³⁷, Xiao-Ru Yang^{37

38}, Siddharth Banka^{39

40}, Katharina Vill⁴¹, Maureen Jacob⁴², Michael Kruer^{43

44}, Peter Skidmore^{43

44

45}, Carolina I Galaz-Montoya^{43

44

46}, Somayeh Bakhtiari^{43

44}, Jessica L Mester⁴⁷, Michael Granato¹¹, Karim-Jean Armache¹², Gregory Costain^{6

7

8

9}, Erica Korb^{2

3}

Affiliations

¹ Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Epigenetics Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Program in Developmental and Stem Cell Biology, Sickkids Research Institute, Toronto, ON M5G 0A4, Canada.
⁶ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada.
⁷ Department of Paediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁹ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON M5G 0A4, Canada.
¹⁰ Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹¹ Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹² Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA.
¹³ Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Santiago 7830490, Chile.
¹⁴ Rare Diseases Program, Center for Genetics and Genomics, Institute for Science and Innovation in Medicine, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Las Condes 7610671, Chile.
¹⁵ Northern Ireland Regional Genetics Service, Belfast BT9 7AB, Northern Ireland.
¹⁶ Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁷ Division of Human Genetics, Rhode Island Hospital, Providence, RI 0290, USA.
¹⁸ Member of ERNBond, Rare Diseases Unit, Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark.
¹⁹ Department of Clinical Genetics, Erasmus MC University Medical Center, GD Rotterdam 3015, The Netherlands.
²⁰ Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, GD Rotterdam 3015, The Netherlands.
²¹ ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, GD Rotterdam 3015, The Netherlands.
²² Genetic Health Queensland, Royal Brisbane & Women's Hospital, Herston, Queensland 4006, Australia.
²³ School of Medicine, Griffith University, Gold Coast, Queensland 4215, Australia.
²⁴ Alberta Children's Hospital, Calgary AB Canada Department of Medical Genetics, Cummings School of Medicine, University of Calgary, Calgary AB T2N 1N4, Canada.
²⁵ Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
²⁶ Institut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpital Pitié Salpêtrière, 75013 Paris, France.
²⁷ Département de Génétique, Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, 75651 Paris, France.
²⁸ Genetic Medico-Diagnostic Laboratory 'Genica', Sofia 1612, Bulgaria.
²⁹ Department of Medical Chemistry and Biochemistry, Medical University Sofia, Sofia 1431, Bulgaria.
³⁰ Clinic of Child Neurology, MHATNP 'St. Naum', Medical University Sofia, Sofia 1431, Bulgaria.
³¹ Department of Genetics, McMaster Children's Hospital, Hamilton, ON L8N 3Z5, Canada.
³² Neuromuscular Unit, Hospital Sant Joan de Deu, Barcelona 08950, Spain.
³³ Laboratory of Neurogenetics and Molecular Medicine, Institut de Recerca Sant Joan de Deu, Barcelona 08950, Spain.
³⁴ Department of Genetics and Reference Center for Developmental Disorders, Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Rouen 76000, France.
³⁵ Department of Genetics, APHP-Robert Debré University Hospital, Paris 75019, France.
³⁶ Laboratoire de biologie médicale multisites SeqOIA-FMG2025, Paris 75014, France.
³⁷ University of Calgary Department of Medical Genetics, Alberta Children's Hospital Research Institute, Calgary, AB T3B 6A8, Canada.
³⁸ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
³⁹ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK.
⁴⁰ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
⁴¹ Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, LMU Hospital, Ludwig-Maximilians-University, Munich 80539, Germany.
⁴² Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany.
⁴³ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
⁴⁴ Departments of Child Health, Neurology, Cellular and Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA.
⁴⁵ College of Health Solutions, Arizona State University, Tempe, AZ 85287, USA.
⁴⁶ Genetics, GIDP PhD Program, Tucson, AZ 85721, USA.
⁴⁷ GeneDx, Gaithersburg, MD 20877, USA.

PMID: 40494548
PMCID: PMC12782159 (available on 2026-06-11)
DOI: 10.1093/brain/awaf212

Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder

Marissa J Maroni et al. Brain. 2026.

. 2026 Jan 8;149(1):343-359.

doi: 10.1093/brain/awaf212.

Authors

Affiliations

¹ Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Epigenetics Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Program in Developmental and Stem Cell Biology, Sickkids Research Institute, Toronto, ON M5G 0A4, Canada.
⁶ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada.
⁷ Department of Paediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁹ Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON M5G 0A4, Canada.
¹⁰ Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹¹ Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹² Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA.
¹³ Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Santiago 7830490, Chile.
¹⁴ Rare Diseases Program, Center for Genetics and Genomics, Institute for Science and Innovation in Medicine, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Las Condes 7610671, Chile.
¹⁵ Northern Ireland Regional Genetics Service, Belfast BT9 7AB, Northern Ireland.
¹⁶ Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁷ Division of Human Genetics, Rhode Island Hospital, Providence, RI 0290, USA.
¹⁸ Member of ERNBond, Rare Diseases Unit, Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark.
¹⁹ Department of Clinical Genetics, Erasmus MC University Medical Center, GD Rotterdam 3015, The Netherlands.
²⁰ Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, GD Rotterdam 3015, The Netherlands.
²¹ ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, GD Rotterdam 3015, The Netherlands.
²² Genetic Health Queensland, Royal Brisbane & Women's Hospital, Herston, Queensland 4006, Australia.
²³ School of Medicine, Griffith University, Gold Coast, Queensland 4215, Australia.
²⁴ Alberta Children's Hospital, Calgary AB Canada Department of Medical Genetics, Cummings School of Medicine, University of Calgary, Calgary AB T2N 1N4, Canada.
²⁵ Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
²⁶ Institut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpital Pitié Salpêtrière, 75013 Paris, France.
²⁷ Département de Génétique, Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, 75651 Paris, France.
²⁸ Genetic Medico-Diagnostic Laboratory 'Genica', Sofia 1612, Bulgaria.
²⁹ Department of Medical Chemistry and Biochemistry, Medical University Sofia, Sofia 1431, Bulgaria.
³⁰ Clinic of Child Neurology, MHATNP 'St. Naum', Medical University Sofia, Sofia 1431, Bulgaria.
³¹ Department of Genetics, McMaster Children's Hospital, Hamilton, ON L8N 3Z5, Canada.
³² Neuromuscular Unit, Hospital Sant Joan de Deu, Barcelona 08950, Spain.
³³ Laboratory of Neurogenetics and Molecular Medicine, Institut de Recerca Sant Joan de Deu, Barcelona 08950, Spain.
³⁴ Department of Genetics and Reference Center for Developmental Disorders, Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Rouen 76000, France.
³⁵ Department of Genetics, APHP-Robert Debré University Hospital, Paris 75019, France.
³⁶ Laboratoire de biologie médicale multisites SeqOIA-FMG2025, Paris 75014, France.
³⁷ University of Calgary Department of Medical Genetics, Alberta Children's Hospital Research Institute, Calgary, AB T3B 6A8, Canada.
³⁸ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
³⁹ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK.
⁴⁰ Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
⁴¹ Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, LMU Hospital, Ludwig-Maximilians-University, Munich 80539, Germany.
⁴² Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany.
⁴³ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
⁴⁴ Departments of Child Health, Neurology, Cellular and Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA.
⁴⁵ College of Health Solutions, Arizona State University, Tempe, AZ 85287, USA.
⁴⁶ Genetics, GIDP PhD Program, Tucson, AZ 85721, USA.
⁴⁷ GeneDx, Gaithersburg, MD 20877, USA.

PMID: 40494548
PMCID: PMC12782159 (available on 2026-06-11)
DOI: 10.1093/brain/awaf212

Abstract

Individuals with monoallelic gain-of-function variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear. Here, we sought to define the effects of partial DOT1L loss by applying bulk and single-nucleus RNA-sequencing, ChIP-sequencing, imaging, multielectrode array recordings and behavioural analysis of zebrafish and multiple mouse models. We present a cohort of 16 individuals (12 females, 4 males) with neurodevelopmental disorders and monoallelic DOT1L variants, including a frameshift deletion, an in-frame deletion, a nonsense, and missense variants clustered in the catalytic domain. We demonstrate that specific variants cause loss of methyltransferase activity. In primary cortical neurons, Dot1l knockdown disrupts transcription of synaptic genes, neuron branching, expression of a synaptic protein and neuronal activity. Further in the cortex of heterozygous Dot1l mice, Dot1l loss causes sex-specific transcriptional responses and H3K79me2 depletion, including within downregulated genes. Lastly, using both zebrafish and mouse models, we found behavioural disruptions that include developmental deficits and sex-specific social behavioural changes. Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts neuronal transcription, neuron morphology and behaviour across multiple models and systems.

Keywords: DOT1L; H3K79me; neurodevelopmental disorders.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Conflict of interest statement

K.V. has received honoraria as an advisory board member, travel expenses and speaker fees from Biogen, Santhera, Orchard, ITF and Novartis, outside the submitted work. J.L.M. is an employee of and may own stock in GeneDx, LLC. All other authors declare they have no competing interests.

Update of

Loss of DOT1L disrupts neuronal transcription, behavior, and leads to a neurodevelopmental disorder.
Maroni MJ, Barton M, Lynch K, Deshwar AR, Campbell PD, Millard J, Lee R, Cohen A, Ahmad R, Paranjapye A, Faundes V, Repetto GM, McKenna C, Shillington AL, Phornphutkul C, Hove HB, Mancini GMS, Schot R, Barakat TS, Richmond CM, Lauzon J, Ibrahim AIE, Nava C, Héron D, van Aalst MMA, Atemin S, Sleptsova M, Aleksandrova I, Todorova A, Watkins DL, Kozenko MA, Natera-de Benito D, Ortez C, Estevez-Arias B, Lecoquierre F, Cassinari K, Guerrot AM, Levy J, Latypova X, Verloes A, Innes AM, Yang XR, Banka S, Vill K, Jacob M, Kruer M, Skidmore P, Galaz-Montoya CI, Bakhtiari S, Mester JL, Granato M, Armache KJ, Costain G, Korb E. Maroni MJ, et al. medRxiv [Preprint]. 2025 Apr 14:2024.10.31.24314716. doi: 10.1101/2024.10.31.24314716. medRxiv. 2025. Update in: Brain. 2026 Jan 8;149(1):343-359. doi: 10.1093/brain/awaf212. PMID: 39574879 Free PMC article. Updated. Preprint.

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Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder

Affiliations

Loss of DOT1L disrupts neuronal transcription and leads to a neurodevelopmental disorder

Authors

Affiliations

Abstract

Conflict of interest statement

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