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Am J Hum Genet. 2019 Jun 6;104(6):1210-1222. doi: 10.1016/j.ajhg.2019.03.021. Epub 2019 May 9.

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

Collaborators (302)

McRae JF, Clayton S, Fitzgerald TW, Kaplanis J, Prigmore E, Rajan D, Sifrim A, Aitken S, Akawi N, Alvi M, Ambridge K, Barrett DM, Bayzetinova T, Jones P, Jones WD, King D, Krishnappa N, Mason LE, Singh T, Tivey AR, Ahmed M, Anjum U, Archer H, Armstrong R, Awada J, Balasubramanian M, Banka S, Baralle D, Barnicoat A, Batstone P, Baty D, Bennett C, Berg J, Bernhard B, Bevan AP, Bitner-Glindzicz M, Blair E, Blyth M, Bohanna D, Bourdon L, Bourn D, Bradley L, Brady A, Brent S, Brewer C, Brunstrom K, Bunyan DJ, Burn J, Canham N, Castle B, Chandler K, Chatzimichali E, Cilliers D, Clarke A, Clasper S, Clayton-Smith J, Clowes V, Coates A, Cole T, Colgiu I, Collins A, Collinson MN, Connell F, Cooper N, Cox H, Cresswell L, Cross G, Crow Y, D'Alessandro M, Dabir T, Davidson R, Davies S, de Vries D, Dean J, Deshpande C, Devlin G, Dixit A, Dobbie A, Donaldson A, Donnai D, Donnelly D, Donnelly C, Douglas A, Douzgou S, Duncan A, Eason J, Ellard S, Ellis I, Elmslie F, Evans K, Everest S, Fendick T, Fisher R, Flinter F, Foulds N, Fry A, Fryer A, Gardiner C, Gaunt L, Ghali N, Gibbons R, Gill H, Goodship J, Goudie D, Gray E, Green A, Greene P, Greenhalgh L, Gribble S, Harrison R, Harrison L, Harrison V, Hawkins R, He L, Hellens S, Henderson A, Hewitt S, Hildyard L, Hobson E, Holden S, Holder M, Holder S, Hollingsworth G, Homfray T, Humphreys M, Hurst J, Hutton B, Ingram S, Irving M, Islam L, Jackson A, Jarvis J, Jenkins L, Johnson D, Jones E, Josifova D, Joss S, Kaemba B, Kazembe S, Kelsell R, Kerr B, Kingston H, Kini U, Kinning E, Kirby G, Kirk C, Kivuva E, Kraus A, Kumar D, Kumar VKA, Lachlan K, Lam W, Lampe A, Langman C, Lees M, Lim D, Longman C, Lowther G, Lynch SA, Magee A, Maher E, Male A, Mansour S, Marks K, Martin K, Maye U, McCann E, McConnell V, McEntagart M, McGowan R, McKay K, McKee S, McMullan DJ, McNerlan S, McWilliam C, Mehta S, Metcalfe K, Middleton A, Miedzybrodzka Z, Miles E, Mohammed S, Montgomery T, Moore D, Morgan S, Morton J, Mugalaasi H, Murday V, Murphy H, Naik S, Nemeth A, Nevitt L, Newbury-Ecob R, Norman A, O'Shea R, Ogilvie C, Ong KR, Park SM, Parker MJ, Patel C, Paterson J, Payne S, Perrett D, Phipps J, Pilz DT, Pollard M, Pottinger C, Poulton J, Pratt N, Prescott K, Price S, Pridham A, Procter A, Purnell H, Quarrell O, Ragge N, Rahbari R, Randall J, Rankin J, Raymond L, Rice D, Robert L, Roberts E, Roberts J, Roberts P, Roberts G, Ross A, Rosser E, Saggar A, Samant S, Sampson J, Sandford R, Sarkar A, Schweiger S, Scott R, Scurr I, Selby A, Seller A, Sequeira C, Shannon N, Sharif S, Shaw-Smith C, Shearing E, Shears D, Sheridan E, Simonic I, Singzon R, Skitt Z, Smith A, Smith K, Smithson S, Sneddon L, Splitt M, Squires M, Stewart F, Stewart H, Straub V, Suri M, Sutton V, Swaminathan GJ, Sweeney E, Tatton-Brown K, Taylor C, Taylor R, Tein M, Temple IK, Thomson J, Tischkowitz M, Tomkins S, Torokwa A, Treacy B, Turner C, Turnpenny P, Tysoe C, Vandersteen A, Varghese V, Vasudevan P, Vijayarangakannan P, Vogt J, Wakeling E, Wallwark S, Waters J, Weber A, Wellesley D, Whiteford M, Widaa S, Wilcox S, Wilkinson E, Williams D, Williams N, Wilson L, Woods G, Wragg C, Wright M, Yates L, Yau M, Nellåker C, Parker M, Firth HV, Wright CF, FitzPatrick DR, Barrett JC, Hurles ME.

Author information

1
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: Anne.ODonnell@childrens.harvard.edu.
2
Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
3
Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Santiago, Chile.
4
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
5
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04103, Germany.
6
Department of Pediatrics, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Quebec, Canada; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica Scienze Materno-Infantili, Università degli studi di Genova, 16126 Genova, Italy; IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
7
Division of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, ON, Canada.
8
Department of Molecular Medicine and Surgery, Centre for Molecular Medicine, Karolinska Institutet, Stockholm 17176, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm 17176, Sweden.
9
Institute of Medical Genetics, University of Zurich, Schlieren-Zurich CH-8952, Switzerland; Neuroscience Center Zurich, University of Zurich and Eidgenössische Technische Hochschule, Zurich 8057, Switzerland.
10
Genetics, Cook Children's Physician Network, Fort Worth, TX 76104, USA.
11
Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, University of Florence, 50139 Florence, Italy.
12
Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Division of Genetics, Rady Children's Hospital of San Diego, San Diego, CA 92123, USA.
13
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.
14
Laboratoire de Génétique Moléculaire et Génomique, Centre Hospitalier Universitaire de Rennes, Rennes 35033, France.
15
Division of Genetics, Rady Children's Hospital of San Diego, San Diego, CA 92123, USA.
16
Department of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75013, France; Groupe de Recherche Clinique Déficience Intellectuelle et Autisme, Sorbonne University, Paris 75006, France.
17
West Midlands Regional Clinical Genetics Service, Birmingham Women's and Children's Hospital, National Health Service Foundation Trust, Birmingham B15 2TG, UK; Birmingham Health Partners, Birmingham Women's and Children's Hospital, National Health Service Foundation Trust, Birmingham B15 2TG, UK.
18
Department of Neurology, Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA.
19
Medical Genetics, University of Siena, 53100 Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.
20
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
21
Service de Génétique Clinique, Centre de Référence Maladies Rares Centre Labellisé Anomalies du Développement-Ouest, Centre Hospitalier Universitaire de Rennes, 35033 Rennes, France.
22
Centre de Génétique Chromosomique, Groupement des Hôpitaux de l'Institut Catholique de Lille Hôpital Saint Vincent de Paul, 59020 Lille, France; Faculté de médecine de l'Université Catholoique de Lille, 59800 Lille, France.
23
Department of Clinical Genetics, Aarhus University Hospital, 8200 Aarhus, Denmark.
24
St. Vincent's Children's Hospital, Indianapolis, IN 46260, USA.
25
Medical Genetic Unit, Italian Hospital of Lugano, Lugano, Switzerland; Università della Svizzera Italiana, 6900 Lugano, Switzerland.
26
Oxford National Institute for Health Research Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
27
Division of Neurology and Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
28
Division of Neurology and Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104 USA; Department of Neuropediatrics, University Medical Center, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
29
GeneDx, Gaithersburg, MD 20877, USA.
30
Service de Génétique Médicale, Hôpital Hôtel-Dieu, Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France.
31
Division of Genetics and Metabolism, Department of Pediatrics, University of Florida, FL 32610, USA.
32
Mendelics Genomic Analysis, Sao Paulo 04013, Brazil.
33
Department of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
34
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
35
Department of Clinical Genetics, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
36
Department of Clinical Genetics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
37
Division of Medical Genetics and Genomics, Spectrum Health, Grand Rapids, MI 49544, USA.
38
Department of Neurology and Neurosurgery, Universidade de Federal de São Paulo, São Paulo 04023, Brazil.
39
Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
40
Department of Neuropediatrics, University Medical Center, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
41
Neuropediatric Unit, Pediatric Department of Southern Switzerland, San Giovanni Hospital, 6500 Bellinzona, Switzerland.
42
Institute of Medical Genetics, University of Zurich, Schlieren-Zurich CH-8952, Switzerland; Neuroscience Center Zurich, University of Zurich and Eidgenössische Technische Hochschule, Zurich 8057, Switzerland; Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurich, CH-8006 Zurich, Switzerland.
43
Department of Pediatrics, Division of Genetics and Metabolism, University of South Florida, Tampa, FL 33606, USA.
44
Section of Pediatric Neurology, Rady Children's Hospital, San Diego, CA 92123, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
45
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA; School of Medicine, University of Missouri, Kansas City, MO 64108, USA.
46
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
47
EA7364 Rares du Developpement Embryonnaire et du Metabolisme, Institut de Genetique Medicale, Centre Hospitalier Universitaire de Lille, University of Lille, F-59000 Lille, France.
48
Department of Pediatrics, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Quebec, Canada.
49
Division of Child Neurology and Inherited Metabolic Diseases, Department of General Paediatrics, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
50
School of Medicine, University of Missouri, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA.
51
Pediatric Neurology and Neurophysiology, Instituto de Neurologia de Goiania, Goiania 74210, Brazil.
52
Department of Medical Genetics, Assistance Publique - Hôpitaux de Marseille, Hôpital d'Enfants de La Timone, 13005 Marseille, France; Marseille Medical Genetics Center, Aix Marseille Univ, Inserm, U1251, Marseille, France.
53
Department of Clinical Genetics, Aarhus University Hospital, 8200 Aarhus, Denmark; Center for Fetal Diagnostics, Aarhus University Hospital, 8200 Aarhus, Denmark.
54
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; Department for Neurosurgery, University of Tübingen, 72076 Tübingen, Germany.
55
Department of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8, ON, Canada.
56
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
57
Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University National Health Service Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
58
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Lance.Rodan@childrens.harvard.edu.

Abstract

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

KEYWORDS:

H3K4 methylation; KMT2E; autism; epilepsy; epileptic encephalopathy; global developmental delay; intellectual disability; neurodevelopmental disorder

PMID:
31079897
PMCID:
PMC6556837
[Available on 2019-12-06]
DOI:
10.1016/j.ajhg.2019.03.021

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