Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.
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| 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.
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| Authors | 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, 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 Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A Trauner, Helio van der Linden Jr, 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 |
| Journal | American journal of human genetics (Am J Hum Genet) Vol. 104 Issue 6 Pg. 1210-1222 (06 06 2019) ISSN: 1537-6605 [Electronic] United States |
| PMID | 31079897 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
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