title: A novelde novoframeshift deletion inEHMT1in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation.
abstract: BACKGROUND
  Kleefstra Syndrome (KS) (MIM# 610253) is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1,GLP).EHMT1(MIM# 607001) encodes a histone methyltransferase that heterodimerizes with EHMT2 (also known as G9a, MIM# 604599), which together are responsible for mono- and dimethylation of H3 lysine 9 (H3K9me1 and -me2), resulting in transcriptional repression of target genes.
  
  
  METHODS
  This report describes an 18-year-old woman with intellectual disability, severely limited speech, hypotonia, microcephaly, and facial dysmorphisms, who was found to have a novelde novosingle-base frameshift deletion inEHMT1.
  
  
  RESULTS
  Functional studies using patient fibroblasts showed decreased H3K9me2 compared to wild-type control cells, thus providing a rapid confirmatory test that complements molecular studies.
  
  
  CONCLUSIONS
  Whole exome sequencing revealed a novel frameshift deletion inEHMT1after a lengthy diagnostic odyssey in this patient. Functional testing using this patient's fibroblasts provides proof-of-concept for the analysis of variants of uncertain significance that are predicted to impact EHMT1 enzymatic activity.
authors.affiliation: Center for Individualized MedicineMayo ClinicJacksonvilleFlorida32224; Department of Health Science ResearchMayo ClinicJacksonvilleFlorida32224.
authors.forename: Patrick R
authors.identifier: 0000-0003-0658-1275
authors.initials: PR
authors.lastname: Blackburn
authors.affiliation: Department of Biochemistry and Molecular Biology Mayo Clinic Rochester Minnesota 55901.
authors.forename: Monique
authors.initials: M
authors.lastname: Williams
authors.affiliation: Center for Individualized MedicineMayo ClinicRochesterMinnesota55901; Department of Health Science ResearchMayo ClinicRochesterMinnesota55901.
authors.forename: Margot A
authors.initials: MA
authors.lastname: Cousin
authors.affiliation: Center for Individualized MedicineMayo ClinicRochesterMinnesota55901; Department of Health Science ResearchMayo ClinicRochesterMinnesota55901.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Boczek
authors.affiliation: Center for Individualized MedicineMayo ClinicRochesterMinnesota55901; Department of Clinical GenomicsMayo ClinicRochesterMinnesota55901.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Beek
authors.affiliation: Laboratory of Epigenetics and Chromatin DynamicsMayo ClinicRochesterMinnesota55901; Division of Gastroenterology and HepatologyMayo ClinicRochesterMinnesota55901.
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Lomberk
authors.affiliation: Laboratory of Epigenetics and Chromatin DynamicsMayo ClinicRochesterMinnesota55901; Division of Gastroenterology and HepatologyMayo ClinicRochesterMinnesota55901.
authors.forename: Raul A
authors.initials: RA
authors.lastname: Urrutia
authors.affiliation: Center for Individualized MedicineMayo ClinicRochesterMinnesota55901; Department of Clinical GenomicsMayo ClinicRochesterMinnesota55901; Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesota55901.
authors.forename: Dusica
authors.initials: D
authors.lastname: Babovic-Vuksanovic
authors.affiliation: Center for Individualized MedicineMayo ClinicRochesterMinnesota55901; Department of Health Science ResearchMayo ClinicRochesterMinnesota55901; Department of Clinical GenomicsMayo ClinicRochesterMinnesota55901; Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesota55901.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
keywords: EHMT1; GLP; Kleefstra Syndrome; functional validation; p.Arg310Aspfs*4; whole exome sequencing