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Intragenic duplication of EHMT1 gene results in Kleefstra syndrome.

ABSTRACT: BACKGROUND:Kleefstra syndrome is characterized by intellectual disability, muscular hypotonia in childhood and typical facial features. It results from either a microdeletion of or a deleterious sequence variant in the gene euchromatic histone-lysine N-methyltransferase 1 (EHMT1) on chromosome 9q34. RESULTS:We report on a 3-year-old girl with characteristic symptoms of Kleefstra syndrome. Array comparative genomic hybridization analysis revealed a 145 kilobases duplication spanning exons 2 to 10 of EHMT1. Sequence analysis characterized it as an intragenic tandem duplication leading to a frame shift with a premature stop codon in EHMT1. CONCLUSIONS:This is the first description of an intragenic duplication of EHMT1 resulting in Kleefstra syndrome.

SUBMITTER: Schwaibold EM

PROVIDER: S-EPMC4209064 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Intragenic duplication of EHMT1 gene results in Kleefstra syndrome.

Schwaibold Eva Maria Christina EM Smogavec Mateja M Hobbiebrunken Elke E Winter Lorenz L Zoll Barbara B Burfeind Peter P Brockmann Knut K Pauli Silke S

Molecular cytogenetics 20141023 1

<h4>Background</h4>Kleefstra syndrome is characterized by intellectual disability, muscular hypotonia in childhood and typical facial features. It results from either a microdeletion of or a deleterious sequence variant in the gene euchromatic histone-lysine N-methyltransferase 1 (EHMT1) on chromosome 9q34.<h4>Results</h4>We report on a 3-year-old girl with characteristic symptoms of Kleefstra syndrome. Array comparative genomic hybridization analysis revealed a 145 kilobases duplication spannin ...[more]

PMID: 25349628

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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.

Dataset Information

Intragenic duplication of EHMT1 gene results in Kleefstra syndrome.

Publications

Intragenic duplication of EHMT1 gene results in Kleefstra syndrome.

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