title: A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors.
abstract: BACKGROUND
  Kleefstra syndrome (KS) is a rare autosomal dominant developmental disability, caused by microdeletions or intragenic mutations within the epigenetic regulator gene EHMT1 (euchromatic histone lysineN-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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  Exome 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.
  
  
  CONCLUSIONS
  These results demonstrate an individualized approach that integrated genetic information and behavior therapies, resulting in a dramatic improvement in regressive behaviors associated with KS.
authors.affiliation: Department of Genetics, Cell Biology & Development University of Minnesota Minneapolis Minnesota.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Mitra
authors.affiliation: Fraser Child & Family Center Minneapolis Minnesota.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dodge
authors.affiliation: Eyebox Tools, Inc.MinneapolisMinnesota; Present address: Jody Van Ness, Institute for Community IntegrationUniversity of MinnesotaMinneapolisMinnesota.
authors.forename: Jody
authors.initials: J
authors.lastname: Van Ness
authors.affiliation: Plymouth Psych Group Plymouth Minnesota.
authors.forename: Israel
authors.initials: I
authors.lastname: Sokeye
authors.affiliation: Department of Genetics, Cell Biology & Development University of Minnesota Minneapolis Minnesota.
authors.forename: Brian
authors.initials: B
authors.lastname: Van Ness
keywords: CYP2D6; EHMT1; Kleefstra syndrome; exome sequencing