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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Anne H. O'Donnell-Luria, Boston Children's Hospital, Broad Institute
  • ,
  • Lynn S. Pais, Broad Institute
  • ,
  • Víctor Faundes, University of Manchester School of Medicine, Universidad Austral de Chile
  • ,
  • Jordan C. Wood, Broad Institute
  • ,
  • Abigail Sveden, Broad Institute
  • ,
  • Victor Luria, Harvard Medical School
  • ,
  • Rami Abou Jamra, Universitat Leipzig
  • ,
  • Andrea Accogli, McGill University, Dipartimento di Pediatria, Università degli Studi di Genova, Genova, Italy., IRCCS Scientific Institute for Research and Care in Oncology
  • ,
  • Kimberly Amburgey, The Hospital for Sick Children
  • ,
  • Britt Marie Anderlid, Karolinska Institutet, Karolinska University Hospital
  • ,
  • Silvia Azzarello-Burri, Physik-Institut, Universitat Zürich-Irchel, ETH Zürich
  • ,
  • Alice A. Basinger, Cook Children's Physician Network
  • ,
  • Claudia Bianchini, University of Florence
  • ,
  • Lynne M. Bird, University of California, San Diego, Rady Children's Hospital
  • ,
  • Rebecca Buchert, University Tübingen
  • ,
  • Wilfrid Carre, University Hospital of Pontchaillou
  • ,
  • Sophia Ceulemans, Rady Children's Hospital
  • ,
  • Perrine Charles, AP-HP Assistance Publique - Hopitaux de Paris, Sorbonne University
  • ,
  • Helen Cox, Birmingham Children’s Hospital
  • ,
  • Lisa Culliton, Children's Mercy Hospital and Clinics
  • ,
  • Aurora Currò, Università degli Studi di Siena, Azienda Ospedaliera Universitaria Senese
  • ,
  • Jeremy F. McRae
  • ,
  • Stephen Clayton
  • ,
  • Tomas W. Fitzgerald
  • ,
  • Joanna Kaplanis
  • ,
  • Elena Prigmore
  • ,
  • Diana Rajan
  • ,
  • Alejandro Sifrim
  • ,
  • Stuart Aitken
  • ,
  • Nadia Akawi
  • ,
  • Mohsan Alvi
  • ,
  • Kirsty Ambridge
  • ,
  • Daniel M. Barrett
  • ,
  • Tanya Bayzetinova
  • ,
  • Philip Jones
  • ,
  • Wendy D. Jones
  • ,
  • Daniel King
  • ,
  • Netravathi Krishnappa
  • ,
  • Laura E. Mason
  • ,
  • Tarjinder Singh
  • ,
  • Adrian R. Tivey
  • ,
  • Munaza Ahmed
  • ,
  • Uruj Anjum
  • ,
  • Hayley Archer
  • ,
  • Ruth Armstrong
  • ,
  • Jana Awada
  • ,
  • Meena Balasubramanian
  • ,
  • Siddharth Banka, University of Manchester School of Medicine, Lewisham and Greenwich NHS Trust
  • ,
  • Elizabeth Jones
  • ,
  • Ida Vogel
  • Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Cambridge

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.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind104
Nummer6
Sider (fra-til)1210-1222
Antal sider13
ISSN0002-9297
DOI
StatusUdgivet - 2019

Se relationer på Aarhus Universitet Citationsformater

ID: 156092925