MCID: KLF001
MIFTS: 36

Kleefstra Syndrome

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

Aliases & Classifications for Kleefstra Syndrome

MalaCards integrated aliases for Kleefstra Syndrome:

Name: Kleefstra Syndrome 12 23 49 24 36 13 41 14 69
9q Subtelomeric Deletion Syndrome 12 23 24
Chromosome 9q Deletion Syndrome 49 24 28
9q34.3 Microdeletion Syndrome 23 49 24
Chromosome 9, Trisomy 9q 69 28
9q34 Deletion Syndrome 12 72
9q- Syndrome 49 24
Chromosome 9q34.3 Deletion Syndrome 49
9q34.3 Deletion Syndrome 24
9q-Syndrome 12
9qstds 23

Characteristics:

GeneReviews:

23
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...

Classifications:



External Ids:

Disease Ontology 12 DOID:0060352
MeSH 41 C563043
KEGG 36 H00907

Summaries for Kleefstra Syndrome

NIH Rare Diseases : 49 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 reproduce.Management 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 hypoplastic left heart syndrome and kleefstra syndrome 1, and has symptoms including seizures An important gene associated with Kleefstra Syndrome is EHMT1 (Euchromatic Histone Lysine Methyltransferase 1), and among its related pathways/superpathways are Lysine degradation and Development NOTCH1-mediated pathway for NF-KB activity modulation. Affiliated tissues include tongue, heart and eye.

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.

Genetics Home Reference : 24 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.

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

UMLS symptoms related to Kleefstra Syndrome:


seizures

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:

# Genetic test Affiliating Genes
1 Chromosome 9q Deletion Syndrome 28 EHMT1
2 Chromosome 9, Trisomy 9q 28

Anatomical Context for Kleefstra Syndrome

MalaCards organs/tissues related to Kleefstra Syndrome:

38
Tongue, Heart, Eye, Testes, Brain, Bone

Publications for Kleefstra Syndrome

Articles related to Kleefstra Syndrome:

(show all 29)
# Title Authors Year
1
Sleep Disturbance as a Precursor of Severe Regression in Kleefstra Syndrome Suggests a Need for Firm and Rapid Pharmacological Treatment. ( 28622207 )
2017
2
Kleefstra Syndrome: The First Case Report From Iran. ( 29228531 )
2017
3
A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation. ( 28361100 )
2017
4
Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities. ( 28498556 )
2017
5
Altered neurite morphology and cholinergic function of induced pluripotent stem cell-derived neurons from a patient with Kleefstra syndrome and autism. ( 28742076 )
2017
6
First prenatal diagnosis of a 'pure' 9q34.3 deletion (Kleefstra syndrome): A case report and literature review. ( 29160022 )
2017
7
A Novel Kleefstra Syndrome Associated Variant that Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. ( 28057753 )
2017
8
A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors. ( 28361099 )
2017
9
A structured assessment of motor function and behavior in patients with Kleefstra syndrome. ( 26808425 )
2016
10
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 )
2016
11
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 )
2016
12
Expanding the phenotypic profile of Kleefstra syndrome: A female with low-average intelligence and childhood apraxia of speech. ( 26833960 )
2016
13
Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome. ( 27123477 )
2016
14
Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling. ( 27373831 )
2016
15
Multiple Coronary Artery Microfistulas in a Girl with Kleefstra Syndrome. ( 27239352 )
2016
16
Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype. ( 26918030 )
2016
17
Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome. ( 26030700 )
2015
18
Pregnancy with de novo 9q34.3 microdeletion and Kleefstra syndrome in the fetus may be associated with an abnormal maternal serum screening result. ( 26384070 )
2015
19
TWINS WITH KLEEFSTRA SYNDROME DUE TO CHROMOSOME 9q34.3 MICRODELETION. ( 26852514 )
2015
20
Severe neonatal presentation of Kleefstra syndrome in a patient with hypoplastic left heart syndrome and 9q34.3 microdeletion. ( 25380126 )
2014
21
Intragenic duplication of EHMT1 gene results in Kleefstra syndrome. ( 25349628 )
2014
22
Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome. ( 23175442 )
2013
23
Reduced Euchromatin histone methyltransferase 1 causes developmental delay, hypotonia, and cranial abnormalities associated with increased bone gene expression in Kleefstra syndrome mice. ( 24362066 )
2013
24
A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. ( 23232695 )
2013
25
Update on Kleefstra Syndrome. ( 22670141 )
2012
26
Characterization of a novel transcript of the EHMT1 gene reveals important diagnostic implications for Kleefstra syndrome. ( 21538692 )
2011
27
Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. ( 21204793 )
2011
28
Kleefstra syndrome in three adult patients: further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course. ( 21910222 )
2011
29
Kleefstra Syndrome ( 20945554 )
1993

Variations for Kleefstra Syndrome

ClinVar genetic disease variations for Kleefstra Syndrome:

6 (show all 21)
# Gene Variation Type Significance SNP ID Assembly Location
1 EHMT1 NM_024757.4(EHMT1): c.3181-80_3233del deletion Pathogenic GRCh37 Chromosome 9, 140708803: 140708935
2 EHMT1 NM_024757.4(EHMT1): c.1533_1536delAGAC (p.Asp512Alafs) deletion Pathogenic rs137852716 GRCh37 Chromosome 9, 140657158: 140657161
3 EHMT1 NM_024757.4(EHMT1): c.1810C> T (p.Gln604Ter) single nucleotide variant Pathogenic rs137852717 GRCh37 Chromosome 9, 140671088: 140671088
4 EHMT1 NM_024757.4(EHMT1): c.1858C> T (p.Arg620Ter) single nucleotide variant Pathogenic rs137852718 GRCh37 Chromosome 9, 140671136: 140671136
5 EHMT1 NM_024757.4(EHMT1): c.2028dupG (p.Pro677Alafs) duplication Pathogenic rs786205128 GRCh37 Chromosome 9, 140672343: 140672343
6 EHMT1 NM_024757.4(EHMT1): c.2193-1G> C single nucleotide variant Pathogenic rs137852720 GRCh37 Chromosome 9, 140674086: 140674086
7 EHMT1 NM_024757.4(EHMT1): c.2863_2864delGT (p.Val955Argfs) deletion Pathogenic rs137852721 GRCh37 Chromosome 9, 140706063: 140706064
8 EHMT1 NM_024757.4(EHMT1): c.2868-1G> A single nucleotide variant Pathogenic rs137852722 GRCh37 Chromosome 9, 140707457: 140707457
9 EHMT1 NM_024757.4(EHMT1): c.2877_2880delTTCT (p.Ser960Glyfs) deletion Pathogenic rs786205129 GRCh37 Chromosome 9, 140707467: 140707470
10 EHMT1 NM_024757.4(EHMT1): c.3180+1G> T single nucleotide variant Pathogenic rs137852724 GRCh37 Chromosome 9, 140707983: 140707983
11 EHMT1 NM_024757.4(EHMT1): c.3229C> T (p.Gln1077Ter) single nucleotide variant Pathogenic rs137852725 GRCh37 Chromosome 9, 140708931: 140708931
12 EHMT1 NM_024757.4(EHMT1): c.3589C> T (p.Arg1197Trp) single nucleotide variant Pathogenic rs137852727 GRCh37 Chromosome 9, 140728849: 140728849
13 EHMT1 NM_024757.4(EHMT1): c.3502C> T (p.Arg1168Ter) single nucleotide variant Pathogenic rs121918301 GRCh37 Chromosome 9, 140712552: 140712552
14 EHMT1 NM_024757.4(EHMT1): c.1413_1425delGGCACCAGGAGAC (p.Pro473Glnfs) deletion Pathogenic rs137852715 GRCh37 Chromosome 9, 140652375: 140652387
15 EHMT1 NM_024757.4(EHMT1): c.3218G> A (p.Cys1073Tyr) single nucleotide variant Pathogenic rs137852726 GRCh37 Chromosome 9, 140708920: 140708920
16 EHMT1 NM_024757.4(EHMT1): c.871C> T (p.Arg291Ter) single nucleotide variant Pathogenic rs137852714 GRCh37 Chromosome 9, 140637870: 140637870
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.1349_1352delAGAA (p.Lys450Serfs) deletion Pathogenic rs886042181 GRCh37 Chromosome 9, 140648723: 140648726
21 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:

7
# 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

Pathways related to Kleefstra Syndrome according to KEGG:

36
# Name Kegg Source Accession
1 Lysine degradation hsa00310

Pathways related to Kleefstra Syndrome according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
10.85 GATAD2B NOTCH1

GO Terms for Kleefstra Syndrome

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

# Name GO ID Score Top Affiliating Genes
1 nucleus GO:0005634 9.43 EHMT1 GATAD2B MBD5 NOTCH1 WIZ ZNF589
2 midbody GO:0030496 9.16 MBD5 WIZ
3 nucleoplasm GO:0005654 9.1 EHMT1 GATAD2B MBD5 NOTCH1 WIZ ZNF589

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

# Name GO ID Score Top Affiliating Genes
1 negative regulation of transcription by RNA polymerase II GO:0000122 8.8 EHMT1 NOTCH1 ZNF589

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

# Name GO ID Score Top Affiliating Genes
1 metal ion binding GO:0046872 9.02 EHMT1 GATAD2B NOTCH1 WIZ ZNF589

Sources for Kleefstra Syndrome

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
27 GO
28 GTR
29 HGMD
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 MedGen
41 MeSH
42 MESH via Orphanet
43 MGI
45 NCI
46 NCIt
47 NDF-RT
50 NINDS
51 Novoseek
53 OMIM
54 OMIM via Orphanet
58 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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