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Kleefstra syndrome (KS) is a rare autosomic dominant genetic disorder caused by euchromatic histone methyltransferase 1 (EHMT1) alterations. Patients mainly present with moderate to severe intellectual disability, a severe delay in/or absence of speech, autism spectrum disorder, childhood hypotonia, neuropsychiatric anomalies, and distinctive dysmorphic features. Here, we report the cases of a male and a female, two younger siblings of three, with asymptomatic parents. An EHMT1 new mutation was identified. Both presented with a typical core phenotype. Some specific features were noted, such as macrocephaly (previously reported) and enuresis (not yet described). Parental analysis identified the mutation in the mosaic state in the father. Reverse phenotyping enabled us to highlight the pauci phenotype features of inguinal hernia, azoospermia, and possible behavioral disorders. This allowed us to adapt his follow-up and genetic counseling for the family. Our three reported cases provide a new description of KS with an intragenic EHMT1 mutation, whereas in the literature most reported cases have EHMT1 deletions. Moreover, in the areas of next-generation sequencing and trio techniques with parental segregation, it is important to remain cautious about disregarding variants based on an autosomal recessive hypothesis.

Kleefstra syndrome (KS) is a genetic syndrome caused by a haploinsufficiency of the EHMT1 gene and characterized by intellectual disability, language disorders, childhood hypotonia and distinct facial features. Only a few cases of first episode of psychosis in KS have already been reported. We describe a young female patient with KS who presented a first episode of psychosis. In a context of an initial diagnosis wavering and a lack of recommendations, this clinical observation illustrates the importance of psychiatric comorbidities and their diagnostic and therapeutic complexity in KS; with a need for multidisciplinary management considering its specific aspects and vulnerabilities.

Spine deformities could be considered a possible manifestation of the childhood hypotonia, typical feature of Kleefstra Syndrome (KS). There is a paucity of literature describing posterior spinal fusion in the Kleefstra syndrome patient. For patients who develop severe scoliotic curve, bracing is often ineffective and surgery is recommended. We report the first corrective surgery for scoliosis in one patient with KS. We describe a case of 13-year-old female with severe developmental scoliosis in KS. Preoperative examination showed a thoracolumbar scoliosis with left convex thoracic curve (T3-T9, 97°) and right convex thoracolumbar curve (T9-L3, 88°). Posterior correction, pedicle screw fixation and bone graft fusion T3-L5 was performed. Postoperatively, the thoracic curve was corrected to 33° while the thoracolumbar one to 26° and better standing posture was obtained. Six month follow-up images showed no loosening of the hardware. The patient is still in our follow-up program. Scoliosis seems to be a rare evenience of the severe hypotonia of patients with KS. We report the first case of scoliosis in KS treated successfully with surgery. Corrective surgery for spinal deformity, such as scoliosis, could help in posture and improve the quality of life especially in complicated patients such as syndromic ones.

Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establish the molecular diagnosis, elucidate the pathogenesis, and provide helpful genetic counseling for affected patients and families. We performed a whole-exome sequencing analysis to search for rare pathogenic mutations co-segregating with schizophrenia transmitted in a dominant inheritance in a two-generation multiplex family. We identified a rare missense mutation H1574R (Histidine1574Arginine, rs199796552) of KMT2C (lysine methyltransferase 2C) co-segregating with affected members in this family. The mutation is a novel deleterious mutation of KMT2C, not reported before in the literature. The KMT2C encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase and involves epigenetic regulation of brain gene expression. Mutations of KMT2C have been found in neurodevelopmental disorders, such as Kleefstra syndrome, intellectual disability, and autism spectrum disorders. Our finding suggests that schizophrenia might be one of the clinical phenotype spectra of KMT2C mutations, and KMT2C might be a novel risk gene for schizophrenia. Nevertheless, the co-segregation of this mutation with schizophrenia in this family might also be due to chance; functional assays of this mutation are needed to address this issue.

Background Over 400 million people worldwide are living with a rare disease. Next Generation Sequencing (NGS) identifies potential disease causative genetic variants. However, many are identified as variants of uncertain significance (VUS) and require functional laboratory validation to determine pathogenicity, and this creates major diagnostic delays. Methods In this study we test a rapid genetic variant assessment pipeline using CRISPR homology directed repair to introduce single nucleotide variants into inducible pluripotent stem cells (iPSCs), followed by neuronal disease modelling, and functional genomics on amplicon and RNA sequencing, to determine cellular changes to support patient diagnosis and identify disease mechanism. Results As proof-of-principle, we investigated an EHMT1 (Euchromatin histone methyltransferase 1; EHMT1 c.3430C > T; p.Gln1144*) genetic variant pathogenic for Kleefstra syndrome and determined changes in gene expression during neuronal progenitor cell differentiation. This pipeline rapidly identified Kleefstra syndrome in genetic variant cells compared to healthy cells, and revealed novel findings potentially implicating the key transcription factors REST and SP1 in disease pathogenesis. Conclusion The study pipeline is a rapid, robust method for genetic variant assessment that will support rare diseases patient diagnosis. The results also provide valuable information on genome wide perturbations key to disease mechanism that can be targeted for drug treatments.

Summary Haploinsufficiency of EHMT1, which encodes histone H3 lysine 9 (H3K9) methyltransferase G9a-like protein (GLP), causes Kleefstra syndrome (KS), a complex disorder of developmental delay and intellectual disability. Here, we examined whether postnatal supply of GLP can reverse the neurological phenotypes seen in Ehmt1Δ/+ mice as a KS model. Ubiquitous GLP supply from the juvenile stage ameliorated behavioral abnormalities in Ehmt1Δ/+ mice. Postnatal neuron-specific GLP supply was not sufficient for the improvement of abnormal behaviors but still reversed the reduction of H3K9me2 and spine number in Ehmt1Δ/+ mice. Interestingly, some inflammatory genes, including IL-1β (Il1b), were upregulated and activated microglial cells increased in the Ehmt1Δ/+ brain, and such phenotypes were also reversed by neuron-specific postnatal GLP supply. Il1b inactivation canceled the microglial and spine number phenotypes in the Ehmt1Δ/+ mice. Thus, H3K9me2 and some neurological phenotypes are reversible, but behavioral abnormalities are more difficult to improve depending on the timing of GLP supply., Graphical abstract, Highlights • Activated microglias increase in a Ehmt1Δ/+ mouse model of Kleefstra syndrome • Diminished H3K9me2 in Ehmt1Δ/+ mouse neurons is reversed by post-natal GLP supply • GLP supply from the juvenile stage can improve abnormal behaviors of Ehmt1Δ/+ mice • Il1b KO cancelles the microglial and spine number phenotypes in the Ehmt1Δ/+ mice, Pathophysiology; Behavioral neuroscience; Molecular neuroscience; Developmental neuroscience

Kleefstra Syndrome is a rare genetic neurodevelopmental disorder characterized by the presence of multiple congenital defects. Patients present a large variety of clinical symptoms: delay in psychomotor and speech development, intellectual disability, muscular hypotension and characteristic facial dysmorphic features. The cause of the syndrome is submicroscopic deletion in the chromosomal region 9q34.3 or an intragenic mutation of the euchromatin histone methyltransferase 1 (EHMT1) gene. Early diagnosis is extremely important for children and their families as it allows quick implementation of appropriate therapeutic management and comprehensive care, which has a great impact on improving the quality of life and prognosis for patients with Kleefstra syndrome. We present the case of a 9-year-old girl with Kleefstra Syndrome in whom the diagnosis of the genetic syndrome was proved at the age of 2 years by chromosome analysis using CGH, which showed deletion in the terminal band 9q34.3 of the long arm of chromosome 9.

SummaryGenetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

AIMS The aim of this retrospective study was to determine the detection rate of the pathogenic copy number variants (CNVs) in a cohort of 33 foetuses - 32 with CHD (congenital heart defects) and 1 with kidney defect, after exclusion of common aneuploidies (trisomy 13, 18, 21, and monosomy X) by karyotyping, Multiplex ligation - dependent probe amplification (MLPA) and chromosomal microarray analysis (CMA). We also assess the effectivity of MLPA as a method of the first tier for quick and inexpensive detection of mutations, causing congenital malformations in foetuses. METHODS MLPA with probe mixes P070, P036 - Telomere 3 and 5, P245 - microdeletions, P250 - DiGeorge syndrome, and P311 - CHD (Congenital heart defects) was performed in 33 samples of amniotic fluid and chorionic villi. CMA was performed in 10 relevant cases. RESULTS Pathogenic CNVs were found in 5 samples: microdeletions in region 22q11.2 (≈2 Mb) in two foetuses, one distal microdeletion of the 22q11.2 region containing genes LZTR1, CRKL, AIFM3 and SNAP29 (≈416 kb) in the foetus with bilateral renal agenesis, 8p23.1 (3.8 Mb) microdeletion syndrome and microdeletion in area 9q34.3 (1.7 Mb, Kleefstra syndrome). MLPA as an initial screening method revealed unambiguously pathogenic CNVs in 15.2 % of samples. CONCLUSION Our study suggests that MLPA and CMA are a reliable and high-resolution technology and should be used as the first-tier test for prenatal diagnosis of congenital heart disease. Determination of the cause of the abnormality is crucial for genetic counselling and further management of the pregnancy.

Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders called Mendelian Disorders of the Epigenetic Machinery (MDEM). This study aims to determine the prevalence of olfactory malformations in a heterogeneous group of subjects with MDEM. We reviewed the clinical data of 35 patients, 20 females and 15 males, with a mean age of 9.52 years (SD 4.99). All patients had a MDEM and an already available high-resolution brain MRI scan. Two experienced neuroradiologists reviewed the MR images, noting abnormalities and classifying olfactory malformations. Main findings included Corpus Callosum, Cerebellar vermis, and olfactory defects. The latter were found in 11/35 cases (31.4%), of which 7/11 had Rubinstein-Taybi syndrome (RSTS), 2/11 had CHARGE syndrome, 1/11 had Kleefstra syndrome (KLFS), and 1/11 had Weaver syndrome (WVS). The irregularities mainly concerned the olfactory bulbs and were bilateral in 9/11 patients. With over 30% of our sample having an olfactory malformation, this study reveals a possible new diagnostic marker for MDEM and links the epigenetic machinery to the development of the olfactory bulbs.

Purpose Guidelines by professional organizations for assessing variant pathogenicity include the recommendation to utilize biologically relevant transcripts, however there is variability in transcript selection by laboratories. Methods We describe three patients whose genomic results were incorrect, because alternative transcripts and tissue expression patterns were not considered by the commercial laboratories. Results In individual 1, a pathogenic coding variant in a brain-expressed isoform of CKDL5 was missed twice on sequencing, because the variant was intronic in the transcripts considered in analysis. In individual 2, a microdeletion affecting KMT2C was not reported on microarray, since deletions of proximal exons in this gene are seen in healthy individuals; however this individual had a more distal deletion involving the brain-expressed KMT2C isoform, giving her a diagnosis of Kleefstra syndrome. Individual 3 was reported to have a pathogenic variant in exon 10 of OFD1 on exome, but had no typical features of the OFD1-related disorders. Since exon 10 is spliced from the more biologically relevant transcripts of OFD1, it was determined that he did not have an OFD1 disorder. Conclusion These examples illustrate the importance of considering alternative transcripts as a potential confounder when genetic results are negative or discordant with the phenotype.

The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.

Objectives To describe the prenatal diagnosis of Kleefstra syndrome (KS), a rare panethnic disorder characterized by mental and developmental delays, distinct facial features, congenital heart and urogenital defects, among others. KS is caused by haploinsusufficiency and loss of function of euchromatin histone methyltransferase 1 (EHMT1) due to deletions or mutations in the chromosomal region 9q34.3. Case presentation The prenatal diagnosis of KS in this case report includes the description of subtle fetal phenotypic abnormalities detected by the fetal ultrasound examination as well as the results of the amniotic fluid microarray analysis that confirmed a fetal denovo deletion in the chromosomal region 9q34.3. These results confirmed the prenatal diagnosis of KS. Conclusions This case is noteworthy because of the late development of very subtle ultrasound abnormalities that triggered prenatal diagnostic studies in amniotic fluid cells, including SNP microarray analysis, that defined the diagnosis of KS. It allowed us to obtain the necessary antepartum consultations with neonatology, other pediatric subspecialties and arrange for the patient’s appropriate place of delivery to optimize the fetal and neonatal outcome.

International audience; Kleefstra syndrome is a disorder caused by a mutation in the EHMT1 gene characterized in humans by general developmental delay, mild to severe intellectual disability and autism. Here, we characterized cumulative memory in the Ehmt1 +/− mouse model using the Object Space Task. We combined conventional behavioral analysis with automated analysis by deep-learning networks, a session-based computational learning model, and a trial-based classifier. Ehmt1 +/− mice showed more anxiety-like features and generally explored objects less, but the difference decreased over time. Interestingly, when analyzing memory-specific exploration, Ehmt1 +/− show increased expression of cumulative memory, but a deficit in a more simple, control memory condition. Using our automatic classifier to differentiate between genotypes, we found that cumulative memory features are better suited for classification than general exploration differences. Thus, detailed behavioral classification with the Object Space Task produced a more detailed behavioral phenotype of the Ehmt1 +/− mouse model.

Kleefstra Syndrome is a rare genetic disorder caused by mutations in EHMT1, Euchromatin Histone Methyl Transferase 1, or deletions encompassing EHMT1 on 9q34.3. Congenital heart defects are among the major findings in patients with 9q34.3 microdeletion/Kleefstra Syndrome along with recognizable facial appearance, developmental delay/intellectual disability including severely delayed or absent speech, hypotonia, seizures, behavioral and sleep abnormalities. Pulmonary hypertension (PH) is a rare condition associated with increased pulmonary artery and right heart pressures that can lead to right heart failure and death if untreated. PH can be idiopathic (IPAH), heritable (HPAH), or associated (APAH) with co-morbid conditions including congenital heart disease (CHD), lung diseases and other metabolic disorders. Genetic factors play important roles in heritable and idiopathic PH development and are particularly relevant but more diverse in etiology in children. PH is also reported in some chromosomal disorders such as Down syndrome in which congenital heart defects are common; however, PH has rarely been reported in patients with 9q34.3 microdeletion/Kleefstra Syndrome. Here, we present 3 patients with 9q34.3 microdeletions with CHD and PH along with review of 5 similar cases reported in the literature and discuss the potential association of PH with Kleefstra syndrome.

Kleefstra syndrome (KS) is a rare genetic condition resulting from either 9q34.3 microdeletions or mutations in the EHMT1 gene located in the same genomic region. To date, approximately 100 patients have been reported, thereby allowing the core phenotype of KS to be defined as developmental delay/intellectual disability, generalized hypotonia, neuropsychiatric anomalies, and a distinctive facial appearance. Here, to further expand the knowledge on genotype and phenotype of this condition, we report 2 novel cases: one patient carrying a 46-kb 9q34.3 deletion and showing macrocephaly never described in KS, and a second patient carrying a classic 9q34.3 deletion, presenting with a previously unreported skeletal feature (postaxial polydactyly of the right foot) and an unusual brain anomaly (olfactory bulb hypoplasia) observed via magnetic resonance imaging. Further, we provide a review of the current literature regarding KS and compare these 2 patients with those previously described, thereby confirming that the genotype-phenotype correlation in KS remains difficult to determine.

Background Kleefstra syndrome type 1 (KS1, OMIM# 610253 ) is a rare autosomal-dominant Mendelian disorder due to heterozygous mutations in the EHMT1 gene or heterozygous deletion of genomic segment of 9q34.3(9qdel). Neurodevelopmental disorder (NDD), intellectual disability (ID) and childhood-onset hypotonia are the well-known phenotypes of KS1. However, these findings were all investigated based on western patients with KS1. Methods KS1 patients were diagnosed by genetic tests. The clinical data was collected and the phenotypes were standardized by compared with patients that previously reported. In silico, conservational and protein structural analysis were performed to assessment the missense variants. Results Ten patients from unrelated families were diagnosed as KS1, who all had NDD and seven of them had global developmental delay (GDD) with significant personal-social disabilities. Among the ten patients, only one (1/10) patient showed neonatal or infantile obesity. The other nine patients were heterozygous variations, including three missense mutations (p.Glu235Gly, p.Asp903Gly, and p.Leu943Pro), three frameshifting mutations (p.Asn1106Lysfs*71, p.Asn1055Tyrfs*121, and p.Lys288Argfs*20), one nonsense mutation (p.Arg246*), one slice site mutation (c.3540+2T > C) and one 9q34.3 deletion in gene of EHMT1. Furthermore, missense mutations showed potential pathogenicity analyzed by in silico. Conclusion We demonstrated that the clinical features in Chinese patients with KS1 were due to EHMT1 defects. We also reported seven novel variants which enriched the mutation spectrum and provided a good understanding of the pathogenesis of KS1.

Kleefstra syndrome (KS) is characterized by developmental delay, intellectual disability, hypotonia and distinct facial features. Additional clinical features include congenital heart defects, cerebral abnormalities, urogenital defects and weight gain. The syndrome is caused by a microdeletion in chromosomal region 9q34.3 (in 85% of cases) or by a mutation in the EHMT1 gene coding for euchromatin histone methyltransferase 1. The prenatal phenotype has not yet been characterized. Herein, we sought to define this phenotype on the basis of a new case report and literature review.

Kleefstra syndrome (KS) (Mendelian Inheritance in Man (MIM) no. 610253), also known as 9q34 deletion syndrome, is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1). The clinical phenotype of KS includes moderate to severe intellectual disability with absent speech, hypotonia, brachycephaly, congenital heart defects, and dysmorphic facial features with hypertelorism, synophrys, macroglossia, protruding tongue, and prognathism. Only a few cases of de novo missense mutations in EHMT1 giving rise to KS have been described. However, some EHMT1 variants have been described in individuals presenting with autism spectrum disorder or mild intellectual disability, suggesting that the phenotypic spectrum resulting from EHMT1 alterations may be quite broad. In this report, we describe two unrelated patients with complex medical histories consistent with KS in whom next generation sequencing identified the same novel c.2426C>T (p.P809L) missense variant in EHMT1. To examine the functional significance of this novel variant, we performed molecular dynamics simulations of the wild type and p.P809L variant, which predicted that the latter would have a propensity to misfold, leading to abnormal histone mark binding. Recombinant EHMT1 p.P809L was also studied using far UV circular dichroism spectroscopy and intrinsic protein fluorescence. These functional studies confirmed the model-based hypotheses and provided evidence for protein misfolding and aberrant target recognition as the underlying pathogenic mechanism for this novel KS-associated variant. This is the first report to suggest that missense variants in EHMT1 that lead to protein misfolding and disrupted histone mark binding can lead to KS.

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.

Contains fulltext : 173890.pdf (Publisher’s version ) (Closed access) Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management. 10 p.

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 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. 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. Conclusion These results demonstrate an individualized approach that integrated genetic information and behavior therapies, resulting in a dramatic improvement in regressive behaviors associated with KS.

Kleefstra syndrome is a disorder caused by a mutation in theEHMT1gene characterized in humans by general developmental delay, mild to severe intellectual disability and autism. Here, we characterized semantic- and episodic-like memory in theEhmt1+/-mouse model using the Object Space Task. We combined conventional behavioral analysis with automated analysis by deep-learning networks, a session-based computational learning model and a trial-based classifier.Ehmt1+/-mice showed more anxiety-like features and generally explored objects less, but the difference decreased over time. Interestingly, when analyzing memory-specific exploration,Ehmt1+/-show increased expression of semantic-like memory, but a deficit in episodic-like memory. A similar dissociation of semantic and episodic memory performance has been previously reported in humans with autism. Using our automatic classifier to differentiate between genotypes, we found that semantic-like memory features are better suited for classification than general exploration differences. Thus, detailed behavioral classification with the Object Space Task produced a more detailed behavioral phenotype of theEhmt1+/-mouse model.One Sentence SummaryEhmt1+/-mice show decreased exploration and episodic-like memory but increased semantic-like memory In the Object Space Task. (143 of 150)

The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.