A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation

Patrick R. Blackburn, Monique Williams, Margot A. Cousin, Nicole J. Boczek, Geoffrey J. Beek, Gwen A. Lomberk, Raul A. Urrutia, Dusica Babovic-Vuksanovic, Eric W. Klee

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 novel de novo single-base frameshift deletion in EHMT1. 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. Conclusion: Whole exome sequencing revealed a novel frameshift deletion in EHMT1 after 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.

Original languageEnglish (US)
Pages (from-to)141-146
Number of pages6
JournalMolecular Genetics and Genomic Medicine
Issue number2
StatePublished - Mar 2017


  • EHMT1
  • GLP
  • Kleefstra Syndrome
  • functional validation
  • p.Arg310Aspfs*4
  • whole exome sequencing

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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