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

  • Am J Hum Genet. 2019 Jun 6;104(6):1210-1222. doi: 10.1016/j.ajhg.2019.03.021.
Anne H O'Donnell-Luria  1 ,  Lynn S Pais  2 ,  Víctor Faundes  3 ,  Jordan C Wood  2 ,  Abigail Sveden  2 ,  Victor Luria  4 ,  Rami Abou Jamra  5 ,  Andrea Accogli  6 ,  Kimberly Amburgey  7 ,  Britt Marie Anderlid  8 ,  Silvia Azzarello-Burri  9 ,  Alice A Basinger  10 ,  Claudia Bianchini  11 ,  Lynne M Bird  12 ,  Rebecca Buchert  13 ,  Wilfrid Carre  14 ,  Sophia Ceulemans  15 ,  Perrine Charles  16 ,  Helen Cox  17 ,  Lisa Culliton  18 ,  Aurora Currò  19 ,  Deciphering Developmental Disorders (DDD) Study  20 ,  Florence Demurger  21 ,  James J Dowling  7 ,  Benedicte Duban-Bedu  22 ,  Christèle Dubourg  14 ,  Saga Elise Eiset  23 ,  Luis F Escobar  24 ,  Alessandra Ferrarini  25 ,  Tobias B Haack  13 ,  Mona Hashim  26 ,  Solveig Heide  16 ,  Katherine L Helbig  27 ,  Ingo Helbig  28 ,  Raul Heredia  29 ,  Delphine Héron  16 ,  Bertrand Isidor  30 ,  Amy R Jonasson  31 ,  Pascal Joset  9 ,  Boris Keren  16 ,  Fernando Kok  32 ,  Hester Y Kroes  33 ,  Alinoë Lavillaureix  21 ,  Xin Lu  34 ,  Saskia M Maas  35 ,  Gustavo H B Maegawa  31 ,  Carlo L M Marcelis  36 ,  Paul R Mark  37 ,  Marcelo R Masruha  38 ,  Heather M McLaughlin  29 ,  Kirsty McWalter  29 ,  Esther U Melchinger  13 ,  Saadet Mercimek-Andrews  39 ,  Caroline Nava  16 ,  Manuela Pendziwiat  40 ,  Richard Person  29 ,  Gian Paolo Ramelli  41 ,  Luiza L P Ramos  32 ,  Anita Rauch  42 ,  Caitlin Reavey  29 ,  Alessandra Renieri  19 ,  Angelika Rieß  13 ,  Amarilis Sanchez-Valle  43 ,  Shifteh Sattar  44 ,  Carol Saunders  45 ,  Niklas Schwarz  46 ,  Thomas Smol  47 ,  Myriam Srour  48 ,  Katharina Steindl  9 ,  Steffen Syrbe  49 ,  Jenny C Taylor  26 ,  Aida Telegrafi  29 ,  Isabelle Thiffault  50 ,  Doris A Trauner  44 ,  Helio van der Linden Jr  51 ,  Silvana van Koningsbruggen  35 ,  Laurent Villard  52 ,  Ida Vogel  53 ,  Julie Vogt  17 ,  Yvonne G Weber  54 ,  Ingrid M Wentzensen  29 ,  Elysa Widjaja  55 ,  Jaroslav Zak  56 ,  Samantha Baxter  2 ,  Siddharth Banka  57 ,  Lance H Rodan  58
PMID: 31079897 DOI: 10.1016/j.ajhg.2019.03.021
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.