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

TitleHeterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.
Publication TypeJournal Article
Year of Publication2019
AuthorsO'Donnell-Luria, AH, Pais, LS, Faundes, V, Wood, JC, Sveden, A, Luria, V, Jamra, RAbou, Accogli, A, Amburgey, K, Anderlid, BMarie, Azzarello-Burri, S, Basinger, AA, Bianchini, C, Bird, LM, Buchert, R, Carré, W, Ceulemans, S, Charles, P, Cox, H, Culliton, L, Currò, A, Demurger, F, Dowling, JJ, Duban-Bedu, B, Dubourg, C, Eiset, SElise, Escobar, LF, Ferrarini, A, Haack, TB, Hashim, M, Heide, S, Helbig, KL, Helbig, I, Heredia, R, Héron, D, Isidor, B, Jonasson, AR, Joset, P, Keren, B, Kok, F, Kroes, HY, Lavillaureix, A, Lu, X, Maas, SM, Maegawa, GHB, Marcelis, CLM, Mark, PR, Masruha, MR, McLaughlin, HM, McWalter, K, Melchinger, EU, Mercimek-Andrews, S, Nava, C, Pendziwiat, M, Person, R, Ramelli, GPaolo, Ramos, LLP, Rauch, A, Reavey, C, Renieri, A, Rieß, A, Sanchez-Valle, A, Sattar, S, Saunders, C, Schwarz, N, Smol, T, Srour, M, Steindl, K, Syrbe, S, Taylor, JC, Telegrafi, A, Thiffault, I, Trauner, DA, van der Linden, H, van Koningsbruggen, S, Villard, L, Vogel, I, Vogt, J, Weber, YG, Wentzensen, IM, Widjaja, E, Zak, J, Baxter, S, Banka, S, Rodan, LH
Corporate AuthorsDeciphering Developmental Disorders (DDD) Study
JournalAm J Hum Genet
Date Published2019 Jun 06

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID31079897
PubMed Central IDPMC6556837
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 HD091846 / HD / NICHD NIH HHS / United States
K12 HD052896 / HD / NICHD NIH HHS / United States
R01 HG009141 / HG / NHGRI NIH HHS / United States
R01 HD073104 / HD / NICHD NIH HHS / United States
/ / Wellcome Trust / United Kingdom