A novel de novo frameshift deletion in EHMT1 in 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 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.

• Authors: 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
• Journal: Molecular genetics & genomic medicine (Mol Genet Genomic Med) Vol. 5 Issue 2 Pg. 141-146 (Mar 2017) ISSN: 2324-9269 [Print] United States
• PMID: 28361100 (Publication Type: Journal Article)