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


Anne H O'Donnell-Luria
Lynn S. Pais
Víctor Faundes
Jordan C. Wood
Abigail Sveden
Victor Luria
Rami Abou Jamra
Andrea Accogli
Kimberly Amburgey
Britt Marie Anderlid
Silvia Azzarello-Burri
Alice A. Basinger
Claudia Bianchini
Lynne M. Bird
Rebecca Buchert
Wilfrid Carre
Sophia Ceulemans
Perrine Charles
Helen Cox
Lisa Culliton, Children's Mercy HospitalFollow
Aurora Currò
Deciphering Developmental Disorders (DDD) Study
Florence Demurger
James J. Dowling
Benedicte Duban-Bedu
Christèle Dubourg
Saga Elise Eiset
Luis F. Escobar
Alessandra Ferrarini
Tobias B. Haack
Mona Hashim
Solveig Heide
Katherine L. Helbig
Ingo Helbig
Raul Heredia
Delphine Héron
Bertrand Isidor
Amy R. Jonasson
Pascal Joset
Boris Keren
Fernando Kok
Hester Y. Kroes
Alinoë Lavillaureix
Xin Lu
Saskia M. Maas
Gustavo H B Maegawa
Carlo L M Marcelis
Paul R. Mark
Marcelo R. Masruha
Heather M. McLaughlin
Kirsty McWalter
Esther U. Melchinger
Saadet Mercimek-Andrews
Caroline Nava
Manuela Pendziwiat
Richard Person
Gian Paolo Ramelli
Luiza L P Ramos
Anita Rauch
Caitlin Reavey
Alessandra Renieri
Angelika Rieß
Amarilis Sanchez-Valle
Shifteh Sattar
Carol J. Saunders, Children's Mercy HospitalFollow
Niklas Schwarz
Thomas Smol
Myriam Srour
Katharina Steindl
Steffen Syrbe
Jenny C. Taylor
Aida Telegrafi
Isabelle Thiffault, Children's Mercy HospitalFollow
Doris A. Trauner
Helio van der Linden
Silvana van Koningsbruggen
Laurent Villard
Ida Vogel
Julie Vogt
Yvonne G. Weber
Ingrid M. Wentzensen
Elysa Widjaja
Jaroslav Zak
Samantha Baxter
Siddharth Banka
Lance H. Rodan

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Publication Date



DOI: 10.1016/j.ajhg.2019.03.021; PMCID: PMC6556837


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.

Journal Title

American journal of human genetics





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MeSH Keywords

Adolescent; Adult; Child; Child, Preschool; DNA-Binding Proteins; Epilepsy; Female; Genetic Variation; Haploinsufficiency; Heterozygote; Humans; Infant; Male; Neurodevelopmental Disorders; Pedigree; Phenotype; Young Adult


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

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