Dataset Information

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.

SUBMITTER: Blackburn PR

PROVIDER: S-EPMC5370226 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

A novel <i>de novo</i> frameshift deletion in <i>EHMT1</i> in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation.

Blackburn Patrick R PR Williams Monique M Cousin Margot A MA Boczek Nicole J NJ Beek Geoffrey J GJ Lomberk Gwen A GA Urrutia Raul A RA Babovic-Vuksanovic Dusica D Klee Eric W EW

Molecular genetics & genomic medicine 20170126 2

<h4>Background</h4>Kleefstra Syndrome (KS) (MIM# 610253) is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (<i>EHMT1,</i> GLP). <i>EHMT1</i> (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.<h4>Methods</h4>This report describes ...[more]

PMID: 28361100

Similar Datasets

Project description:BackgroundKleefstra syndrome (KS) is a rare autosomal dominant developmental disability, caused by microdeletions or intragenic mutations within the epigenetic regulator gene EHMT1 (euchromatic histone lysine N-methyltransferase 1). In addition to common features of autism, young adult regressive behaviors have been reported. However, the genetic downstream effects of the reported deletions or mutations on KS phenotype have not yet been completely explored. While genetic backgrounds affecting drug metabolism can have a profound effect on therapeutic interventions, pharmacogenomic variations are seldom considered in directing psychotropic therapies.MethodsIn this report, we used next-generation sequencing (exome sequencing and high-throughput RNA sequencing) in a patient and his parents to identify causative genetic variants followed by pharmacogenomics-guided clinical decision-making for making positive changes toward his treatment strategies. The patient had an early autism diagnosis and showed significant regressive behaviors and physical aberrations at age 23.ResultsExome sequencing identified a novel, de novo splice site variant NM_024757.4: c.2750-1G>T in EHMT1, a candidate gene for Kleefstra syndrome, in the patient that results in exon skipping and downstream frameshift and termination. Gene expression results from the patient showed, when compared to his parents, there was a significant decreased expression of several reported gene variants associated with autism risk. Further, using a pharmacogenomics genotyping panel, we discovered that the patient had the CYP2D6 nonfunctioning variant genotype *4/*4 that results in very low metabolic activity on a number of psychotropic drugs, including fluvoxamine which he was prescribed. As reported here, a change in psychotropic drugs and intense behavior therapies resulted in a significant reversal of the regressive behaviors and physical aberrations.ConclusionThese results demonstrate an individualized approach that integrated genetic information and behavior therapies, resulting in a dramatic improvement in regressive behaviors associated with KS.