Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy
Authors: O'Donnell-Luria Anne H , Pais Lynn S , Faundes Victor , Wood Jordan C , Sveden Abigail , Luria Victor , Abou Jamra Rami , Accogli Andrea , Amburgey Kimberly , Anderlid Britt-Marie , Azzarello-Burri Silvia , Basinger Alice A , Bianchini Claudia , Bird Lynn M , Buchert Rebecca , Carre Wilfrid , Ceulemans Sophia , Charles Perrine , Cox Helen , Culliton Lisa , Currò Aurora ,   Deciphering Developmental Disorders (DDD) Study, Demurger Florence , Dowling James J , Duban-Bedu Benedicte , Dubourg Christele , Escobar Luis F , Ferrarini Alessandra , Haack Tobias B , Hashim Mona , Heide Solveig , Helbig Katherine L , Helbig Ingo , Heredia Raul , Heron Delphine , Isidor Bertrand , Jonasson Amy R , Joset Pascal , Keren Boris , Kok Fernando , Kroes Hester Y , Lavillaureix Alinoë , Lu Xin , Maas Saskia , Maegawa Gustavo HB , Marcelis Carlo LM , Eiset Saga Elise , Mark Paul R , Masruha Mercelo R , McLaughlin Heather M , McWalter Kirsty , Melchinger Esther U , Mercimek-Andrews Saadet , Nava Caroline , Pendziwiat Manuela , Person Richard , Ramelli Gian Paolo Paolo , Ramos Luiza LP , Rauch Anita , Reavey Caitlin , Renieri Alessandra , Rie&szlig Angelika , Sanchez-Valle Amarilis , Sattar Shifteh , Saunders Carol , Schwarz Niklas , Smol Thomas , Srour Myriam , Steindl Katharina , Syrbe Steffen , Taylor Jenny C , Telegrafi Aida , Thiffault Isabelle , Trauner Doris A , van der Linden Helio , van Koningsbruggen Silvana , Villard Laurent , Vogel Ida , Vogt Julie , Weber Yvonne G , Wentzensen Ingrid M , Widjaja Elysa , Zak Jaroslav , Baxter Samantha , Banka Siddharth , Rodan Lance H 
Published: March 2019

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 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. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy 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 may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.