Kleefstra Syndrome

Categories: Genetic diseases, Rare diseases, Neuronal diseases, Fetal diseases

Aliases & Classifications for Kleefstra Syndrome

MalaCards integrated aliases for Kleefstra Syndrome:

Name: Kleefstra Syndrome 54 12 23 50 24 25 56 71 13 42 14 69
9q Subtelomeric Deletion Syndrome 12 23 24 25
9q34.3 Microdeletion Syndrome 23 50 24 25
Chromosome 9q34.3 Deletion Syndrome 50 24 71
Chromosome 9q Deletion Syndrome 50 25 29
9q- Syndrome 50 25 71
9qstds 23 24
Chromosome 9q Subtelomeric Deletion Syndrome 71
9q34.3 Deletion Syndrome 25
Chromosome 9, Trisomy 9q 69
9q34 Deletion Syndrome 12
9q-Syndrome 12
Klests 71


Orphanet epidemiological data:

kleefstra syndrome
Inheritance: Autosomal dominant; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal; Age of death: elderly;


autosomal dominant

de novo mutation in most cases
many cases have submicroscopic subtelomeric deletions of chromosome 9q leading to haploinsufficiency of ehmt1


kleefstra syndrome:
Inheritance autosomal dominant inheritance sporadic


Penetrance Penetrance is likely to be 100%: clinical features of kleefstra syndrome are apparent in all individuals with inactivation of one ehmt1 allele, although the extent and severity of clinical findings vary among individuals...


Summaries for Kleefstra Syndrome

NIH Rare Diseases : 50 the following summary is from orphanet, a european reference portal for information on rare diseases and orphan drugs.orpha number: 261494disease definitionkleefstra syndrome (ks) is a genetic disorder characterized by intellectual disability, childhood hypotonia, severe expressive speech delay and a distinctive facial appearance with a spectrum of additional clinical features.epidemiologythe prevalence is unknown. to date, 114 cases have been described.clinical descriptionpatients with ks have a distinctive facial appearance comprised of brachy-microcephaly, midface hypoplasia, unusual eyebrow shape, synophyrs, cupid bow upper lip, full everted lower lip, protruding tongue and prognathism. with age, facial features become coarser and dental anomalies, like retention of primary dentition, are seen. birth weight is normal but half of children go on to suffer from obesity. childhood hypotonia causes motor delay but most children walk independently by age 2 or 3. most patients have moderate to severe intellectual disability with expressive speech delay and little speech development (nonverbal communication is possible). additional features include congenital heart malformations (interauricular communication, ventricular septal defects, bicuspid aortic valve, pulmonary valve stenosis (see these terms)), genital defects in males (hypospadias, cryptorchidism, micropenis), renal defects (hydronephrosis, chronic renal insufficiency, renal cysts, vesico-ureteral reflux), epilepsy, recurrent infections, severe constipation and hearing problems. in adolescence/adulthood behavioral problems (aggressive/emotional outbursts, attention deficit problems, self-mutilation and severe sleep disturbances) can begin. autistic-like behavior can be noted earlier in some children. recurrent pulmonary infections, overweight and behavioral problems seem to be reported more often in those with ks due to a point mutation, whereas microcephaly, short stature, respiratory complications and tracheomalacia are more frequently seen in those with ks due to a 9q34 microdeletion.etiologyks is caused by either a point mutation in the euchromatic histone-lysine n-methyltransferase 1 (ehmt1) gene (rarely) or by a microdeletion in the chromosome region 9q34.3 (seen in >85% of cases), leading to the loss of the entire gene. this gene encodes an enzyme that modifies histone function and is essential for normal development. larger deletions (>1mb) are associated with more severe symptoms.diagnostic methodsdiagnosis of ks is determined by the presence of the characteristic clinical features and molecular genetic testing. a microarray detects any duplications/deletions. fluorescent in situ hybridization (fish) or multiplex ligation-dependent probe amplification (mlpa) can then be used to detect the specific 9q34.3 deletion seen in ks. sequencing of the entire coding region of the ehmt1 gene can detect sequence variants.differential diagnosisdifferential diagnoses include down, pitt-hopkins, smith-magenis, rett and 2q23.1 microdeletion syndromes (see these terms).antenatal diagnosisantenatal diagnosis is offered to unaffected parents of a child with ks as they have a higher risk of having another child with this disorder.genetic counselingmost reported cases have been de novo but familial recurrence has been seen. ks has a theoretical autosomal dominant transmission, but the majority of patients do not and treatmenttreatment requires a multidisciplinary team, specializing in patients with intellectual deficiencies. special education and vocational training along with speech therapy, physical and occupational therapy and sensory integration therapy are recommended from an early age. standard treatment is necessary for those with renal, cardiac and urologic issues and for hearing loss. psychiatric care along with behavioral intervention therapy may be needed. cardiac screening (for the presence of arrhythmias) as well as intestinal and renal/urologic monitoring is recommended. medical follow-up is life-long.prognosisthe prognosis of ks is variable but in most cases it is not a life-threatening disease.visit the orphanet disease page for more resources. last updated: 8/1/2012

MalaCards based summary : Kleefstra Syndrome, also known as 9q subtelomeric deletion syndrome, is related to kleefstra syndrome due to 9q34 microdeletion and kleefstra syndrome due to a point mutation, and has symptoms including macroglossia, brachydactyly and recurrent respiratory infections. An important gene associated with Kleefstra Syndrome is EHMT1 (Euchromatic Histone Lysine Methyltransferase 1), and among its related pathways/superpathways are Gene Expression and Chromatin organization. Affiliated tissues include heart, tongue and testes.

UniProtKB/Swiss-Prot : 71 Kleefstra syndrome: A syndrome characterized by severe mental retardation, hypotonia, brachy(micro)cephaly, and facial dysmorphisms. Additionally, congenital heart defects, urogenital defects, epilepsy and behavioral problems are frequently observed.

Genetics Home Reference : 25 Kleefstra syndrome is a disorder that involves many parts of the body. Characteristic features of Kleefstra syndrome include developmental delay and intellectual disability, severely limited or absent speech, and weak muscle tone (hypotonia). Affected individuals also have an unusually small head size (microcephaly) and a wide, short skull (brachycephaly). Distinctive facial features include eyebrows that grow together in the middle (synophrys), widely spaced eyes (hypertelorism), a sunken appearance of the middle of the face (midface hypoplasia), nostrils that open to the front rather than downward (anteverted nares), a protruding jaw (prognathism), rolled out (everted) lips, and a large tongue (macroglossia). Affected individuals may have a high birth weight and childhood obesity.

OMIM : 54
Submicroscopic subtelomeric deletions of chromosome 9q are associated with a recognizable mental retardation syndrome (Harada et al., 2004; Iwakoshi et al., 2004; Stewart et al., 2004; Neas et al., 2005). Common features in patients with 9q subtelomeric deletion syndrome are severe mental retardation, hypotonia, brachy(micro)cephaly, epileptic seizures, flat face with hypertelorism, synophrys, anteverted nares, everted lower lip, carp mouth with macroglossia, and heart defects. (610253)

Disease Ontology : 12 A syndrome characterized by childhood hypotonia, a distinctive facial appearance, speech impediments and developmental disability, as well as epilepsy, congenital and urogenetic defects, microcephaly, corpulence, and psychiatric disorders. It is caused either by a microdeletion in the chromosome region 9q34.3 or by a point mutation in the EHMT1 gene located in that region.

Wikipedia : 72 9q34 deletion syndrome, also known as Kleefstra syndrome, is a rare genetic disorder. Terminal deletions... more...

GeneReviews: NBK47079

Related Diseases for Kleefstra Syndrome

Graphical network of the top 20 diseases related to Kleefstra Syndrome:

Diseases related to Kleefstra Syndrome

Symptoms & Phenotypes for Kleefstra Syndrome

Symptoms via clinical synopsis from OMIM:


Neurologic- Central Nervous System:
mental retardation, severe

Head And Neck- Ears:
malformed ears
hearing loss

Skeletal- Hands:
single transverse palmar creases

Head And Neck- Eyes:
upslanting palpebral fissures

Neurologic- Behavioral Psychiatric Manifestations:
aggressive behavior
stereotypic movements
sleep disorders
behavioral problems
obsessive-compulsive disorder

Growth- Weight:

Head And Neck- Face:
coarse facies
midface hypoplasia
flat face

Head And Neck- Mouth:
everted lower lip
carp-shaped mouth

Head And Neck- Head:

Head And Neck- Nose:
anteverted nares

Skin Nails & Hair- Hair:

Cardiovascular- Heart:
conotruncal heart defects

Clinical features from OMIM:


Human phenotypes related to Kleefstra Syndrome:

32 (show all 44)
id Description HPO Frequency HPO Source Accession
1 macroglossia 32 frequent (33%) HP:0000158
2 brachydactyly 32 HP:0001156
3 recurrent respiratory infections 32 frequent (33%) HP:0002205
4 intellectual disability, severe 32 HP:0010864
5 seizures 32 very rare (1%) HP:0001250
6 microcephaly 32 very rare (1%) HP:0000252
7 micropenis 32 frequent (33%) HP:0000054
8 coarse facial features 32 frequent (33%) HP:0000280
9 hypertelorism 32 frequent (33%) HP:0000316
10 hypospadias 32 frequent (33%) HP:0000047
11 short nose 32 HP:0003196
12 anteverted nares 32 frequent (33%) HP:0000463
13 gastroesophageal reflux 32 occasional (7.5%) HP:0002020
14 cryptorchidism 32 frequent (33%) HP:0000028
15 talipes equinovarus 32 occasional (7.5%) HP:0001762
16 intellectual disability 32 hallmark (90%) HP:0001249
17 autism 32 frequent (33%) HP:0000717
18 aggressive behavior 32 frequent (33%) HP:0000718
19 synophrys 32 frequent (33%) HP:0000664
20 brachycephaly 32 frequent (33%) HP:0000248
21 apathy 32 very rare (1%) HP:0000741
22 midface retrusion 32 HP:0011800
23 flat face 32 HP:0012368
24 obesity 32 frequent (33%) HP:0001513
25 muscular hypotonia 32 hallmark (90%) HP:0001252
26 protruding tongue 32 frequent (33%) HP:0010808
27 malar flattening 32 frequent (33%) HP:0000272
28 obsessive-compulsive behavior 32 HP:0000722
29 single transverse palmar crease 32 HP:0000954
30 hearing impairment 32 very rare (1%) HP:0000365
31 delayed speech and language development 32 frequent (33%) HP:0000750
32 sleep disturbance 32 frequent (33%) HP:0002360
33 tracheobronchomalacia 32 very rare (1%) HP:0002786
34 everted lower lip vermilion 32 frequent (33%) HP:0000232
35 conotruncal defect 32 very rare (1%) HP:0001710
36 mandibular prognathia 32 frequent (33%) HP:0000303
37 stereotypy 32 frequent (33%) HP:0000733
38 abnormality of the pinna 32 frequent (33%) HP:0000377
39 upslanted palpebral fissure 32 frequent (33%) HP:0000582
40 abnormal renal morphology 32 very rare (1%) HP:0012210
41 persistence of primary teeth 32 occasional (7.5%) HP:0006335
42 u-shaped upper lip vermilion 32 frequent (33%) HP:0010806
43 abnormal heart morphology 32 HP:0001627
44 natal tooth 32 occasional (7.5%) HP:0000695

UMLS symptoms related to Kleefstra Syndrome:


Drugs & Therapeutics for Kleefstra Syndrome

Search Clinical Trials , NIH Clinical Center for Kleefstra Syndrome

Cochrane evidence based reviews: kleefstra syndrome

Genetic Tests for Kleefstra Syndrome

Genetic tests related to Kleefstra Syndrome:

id Genetic test Affiliating Genes
1 Chromosome 9q Deletion Syndrome 29
2 Kleefstra Syndrome 24 EHMT1

Anatomical Context for Kleefstra Syndrome

MalaCards organs/tissues related to Kleefstra Syndrome:

Heart, Tongue, Testes, Eye, Bone, Brain

Publications for Kleefstra Syndrome

Articles related to Kleefstra Syndrome:

(show all 27)
id Title Authors Year
Sleep Disturbance as a Precursor of Severe Regression in Kleefstra Syndrome Suggests a Need for Firm and Rapid Pharmacological Treatment. ( 28622207 )
A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation. ( 28361100 )
A Novel Kleefstra Syndrome Associated Variant that Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. ( 28057753 )
Altered neurite morphology and cholinergic function of induced pluripotent stem cell-derived neurons from a patient with Kleefstra syndrome and autism. ( 28742076 )
A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors. ( 28361099 )
Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities. ( 28498556 )
Expanding the phenotypic profile of Kleefstra syndrome: A female with low-average intelligence and childhood apraxia of speech. ( 26833960 )
Multiple Coronary Artery Microfistulas in a Girl with Kleefstra Syndrome. ( 27239352 )
Establishment of EHMT1 mutant induced pluripotent stem cell (iPSC) line from a 11-year-old Kleefstra syndrome (KS) patient with autism and normal intellectual performance. ( 27789404 )
Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance. ( 27651234 )
Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype. ( 26918030 )
A structured assessment of motor function and behavior in patients with Kleefstra syndrome. ( 26808425 )
Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling. ( 27373831 )
Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome. ( 27123477 )
Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome. ( 26030700 )
Pregnancy with de novo 9q34.3 microdeletion and Kleefstra syndrome in the fetus may be associated with an abnormal maternal serum screening result. ( 26384070 )
Severe neonatal presentation of Kleefstra syndrome in a patient with hypoplastic left heart syndrome and 9q34.3 microdeletion. ( 25380126 )
Intragenic duplication of EHMT1 gene results in Kleefstra syndrome. ( 25349628 )
A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. ( 23232695 )
Reduced Euchromatin histone methyltransferase 1 causes developmental delay, hypotonia, and cranial abnormalities associated with increased bone gene expression in Kleefstra syndrome mice. ( 24362066 )
Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome. ( 23175442 )
Update on Kleefstra Syndrome. ( 22670141 )
Kleefstra syndrome in three adult patients: further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course. ( 21910222 )
Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. ( 21204793 )
Characterization of a novel transcript of the EHMT1 gene reveals important diagnostic implications for Kleefstra syndrome. ( 21538692 )
Kleefstra Syndrome ( 20945554 )

Variations for Kleefstra Syndrome

UniProtKB/Swiss-Prot genetic disease variations for Kleefstra Syndrome:

id Symbol AA change Variation ID SNP ID
1 EHMT1 p.Cys1075Tyr VAR_069183

ClinVar genetic disease variations for Kleefstra Syndrome:

6 (show all 23)
id Gene Variation Type Significance SNP ID Assembly Location
1 EHMT1 NM_024757.4(EHMT1): c.3502C> T (p.Arg1168Ter) single nucleotide variant Pathogenic rs121918301 GRCh37 Chromosome 9, 140712552: 140712552
2 EHMT1 NM_024757.4(EHMT1): c.1413_1425delGGCACCAGGAGAC (p.Pro473Glnfs) deletion Pathogenic rs137852715 GRCh37 Chromosome 9, 140652375: 140652387
3 EHMT1 NM_024757.4(EHMT1): c.3218G> A (p.Cys1073Tyr) single nucleotide variant Pathogenic rs137852726 GRCh37 Chromosome 9, 140708920: 140708920
4 EHMT1 NM_024757.4(EHMT1): c.871C> T (p.Arg291Ter) single nucleotide variant Pathogenic rs137852714 GRCh37 Chromosome 9, 140637870: 140637870
5 EHMT1 NM_024757.4(EHMT1): c.3181-80_3233del deletion Pathogenic GRCh37 Chromosome 9, 140708803: 140708935
6 EHMT1 NM_024757.4(EHMT1): c.1533_1536delAGAC (p.Asp512Alafs) deletion Pathogenic rs137852716 GRCh37 Chromosome 9, 140657158: 140657161
7 EHMT1 NM_024757.4(EHMT1): c.1810C> T (p.Gln604Ter) single nucleotide variant Pathogenic rs137852717 GRCh37 Chromosome 9, 140671088: 140671088
8 EHMT1 NM_024757.4(EHMT1): c.1858C> T (p.Arg620Ter) single nucleotide variant Pathogenic rs137852718 GRCh37 Chromosome 9, 140671136: 140671136
9 EHMT1 NM_024757.4(EHMT1): c.2028dupG (p.Pro677Alafs) duplication Pathogenic rs786205128 GRCh37 Chromosome 9, 140672343: 140672343
10 EHMT1 NM_024757.4(EHMT1): c.2193-1G> C single nucleotide variant Pathogenic rs137852720 GRCh37 Chromosome 9, 140674086: 140674086
11 EHMT1 NM_024757.4(EHMT1): c.2863_2864delGT (p.Val955Argfs) deletion Pathogenic rs137852721 GRCh37 Chromosome 9, 140706063: 140706064
12 EHMT1 NM_024757.4(EHMT1): c.2868-1G> A single nucleotide variant Pathogenic rs137852722 GRCh37 Chromosome 9, 140707457: 140707457
13 EHMT1 NM_024757.4(EHMT1): c.2877_2880delTTCT (p.Ser960Glyfs) deletion Pathogenic rs786205129 GRCh37 Chromosome 9, 140707467: 140707470
14 EHMT1 NM_024757.4(EHMT1): c.3180+1G> T single nucleotide variant Pathogenic rs137852724 GRCh37 Chromosome 9, 140707983: 140707983
15 EHMT1 NM_024757.4(EHMT1): c.3229C> T (p.Gln1077Ter) single nucleotide variant Pathogenic rs137852725 GRCh37 Chromosome 9, 140708931: 140708931
16 EHMT1 NM_024757.4(EHMT1): c.3589C> T (p.Arg1197Trp) single nucleotide variant Pathogenic rs137852727 GRCh37 Chromosome 9, 140728849: 140728849
17 EHMT1 NM_024757.4(EHMT1): c.391delG (p.Ala131Profs) deletion Pathogenic rs797045043 GRCh37 Chromosome 9, 140611383: 140611383
18 EHMT1 NM_024757.4(EHMT1): c.3413G> A (p.Trp1138Ter) single nucleotide variant Pathogenic rs886037776 GRCh38 Chromosome 9, 137817477: 137817477
19 EHMT1 NM_024757.4(EHMT1): c.673C> T (p.Arg225Ter) single nucleotide variant Pathogenic rs879255531 GRCh37 Chromosome 9, 140622831: 140622831
20 EHMT1 NM_024757.4(EHMT1): c.3310G> A (p.Glu1104Lys) single nucleotide variant Likely pathogenic rs886041093 GRCh37 Chromosome 9, 140710450: 140710450
21 EHMT1 NM_024757.4(EHMT1): c.1349_1352delAGAA (p.Lys450Serfs) deletion Pathogenic rs886042181 GRCh37 Chromosome 9, 140648723: 140648726
22 EHMT1 NM_024757.4(EHMT1): c.3583_3594delGTCAGCCGGTTC (p.Val1195_Phe1198del) deletion Likely pathogenic GRCh37 Chromosome 9, 140728843: 140728854
23 EHMT1 NM_024757.4(EHMT1): c.2214_2230dup (p.Phe744Serfs) duplication Pathogenic GRCh38 Chromosome 9, 137779656: 137779672

Copy number variations for Kleefstra Syndrome from CNVD:

id CNVD ID Chromosom Start End Type Gene Symbol CNVD Disease
1 247195 9 129300000 140273252 Deletion EHMT1 Kleefstra Syndrome
2 247196 9 129300000 140273252 Deletion EHMT1 Kleefstra syndrome
3 248681 9 136600000 140273252 Deletion Kleefstra syndrome
4 249316 9 139633264 139850399 Mutation EHMT1 Kleefstra syndrome

Expression for Kleefstra Syndrome

Search GEO for disease gene expression data for Kleefstra Syndrome.

Pathways for Kleefstra Syndrome

GO Terms for Kleefstra Syndrome

Cellular components related to Kleefstra Syndrome according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 nucleus GO:0005634 9.43 EHMT1 EHMT2 GATAD2B NOTCH1 WIZ ZNF589
2 nucleoplasm GO:0005654 9.1 EHMT1 EHMT2 GATAD2B NOTCH1 WIZ ZNF589

Biological processes related to Kleefstra Syndrome according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 negative regulation of transcription from RNA polymerase II promoter GO:0000122 9.58 EHMT1 EHMT2 NOTCH1
2 regulation of signal transduction by p53 class mediator GO:1901796 9.46 EHMT1 EHMT2
3 histone lysine methylation GO:0034968 9.43 EHMT1 EHMT2
4 DNA methylation GO:0006306 9.37 EHMT1 EHMT2
5 histone methylation GO:0016571 9.32 EHMT1 EHMT2
6 response to fungicide GO:0060992 9.26 EHMT1 EHMT2
7 histone H3-K27 methylation GO:0070734 9.16 EHMT1 EHMT2
8 peptidyl-lysine dimethylation GO:0018027 8.96 EHMT1 EHMT2
9 histone H3-K9 methylation GO:0051567 8.62 EHMT1 EHMT2

Molecular functions related to Kleefstra Syndrome according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 metal ion binding GO:0046872 9.8 EHMT1 EHMT2 GATAD2B NOTCH1 WIZ ZNF589
2 p53 binding GO:0002039 9.4 EHMT1 EHMT2
3 histone-lysine N-methyltransferase activity GO:0018024 9.37 EHMT1 EHMT2
4 protein-lysine N-methyltransferase activity GO:0016279 9.26 EHMT1 EHMT2
5 C2H2 zinc finger domain binding GO:0070742 9.16 EHMT1 EHMT2
6 histone methyltransferase activity (H3-K27 specific) GO:0046976 8.96 EHMT1 EHMT2
7 histone methyltransferase activity (H3-K9 specific) GO:0046974 8.62 EHMT1 EHMT2

Sources for Kleefstra Syndrome

9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
28 GO
29 GTR
32 HPO
33 ICD10
34 ICD10 via Orphanet
38 LifeMap
40 MedGen
42 MeSH
43 MESH via Orphanet
44 MGI
46 NCI
47 NCIt
52 Novoseek
55 OMIM via Orphanet
59 PubMed
66 SNOMED-CT via Orphanet
68 Tocris
70 UMLS via Orphanet
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