MCID: KLF001
MIFTS: 40

Kleefstra Syndrome

Categories: Eye diseases, Fetal diseases, Genetic diseases, Mental diseases, Metabolic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Kleefstra Syndrome

Summaries for Kleefstra Syndrome

NIH Rare Diseases : 52 The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 261494 Definition Kleefstra 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. Epidemiology The prevalence is unknown. To date, 114 cases have been described. Clinical description Patients 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. Etiology KS 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 methods Diagnosis 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 diagnosis Differential diagnoses include Down, Pitt-Hopkins, Smith-Magenis, Rett and 2q23.1 microdeletion syndromes (see these terms). Antenatal diagnosis Antenatal 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 counseling Most 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 treatment Treatment 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. Prognosis The prognosis of KS is variable but in most cases it is not a life-threatening disease. Visit the Orphanet disease page for more resources.

MalaCards based summary : Kleefstra Syndrome, also known as chromosome 9q deletion syndrome, is related to kleefstra syndrome due to a point mutation 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 PKMTs methylate histone lysines. Affiliated tissues include heart, tongue and eye, and related phenotypes are malar flattening and hypertelorism

Disease Ontology : 12 A syndrome that is characterized by developmental delay and intellectual disability, severely limited or absent speech, and weak muscle tone.

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. People with Kleefstra syndrome may also have structural brain abnormalities, congenital heart defects, genitourinary abnormalities, seizures, and a tendency to develop severe respiratory infections. During childhood they may exhibit features of autism or related developmental disorders affecting communication and social interaction. In adolescence, they may develop a general loss of interest and enthusiasm (apathy) or unresponsiveness (catatonia).

KEGG : 36 Kleefstra syndrome (KLEFS), also known as the 9q subtelomeric deletion syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. About 75% of Kleefstra syndrome is caused by microdeletion of 9q34.3 and 25% by intragenic EHMT1 mutation. Recently, a few patients with loss of function mutations affecting the histone methyltransferase KMT2C were reported.

GeneReviews: NBK47079

Related Diseases for Kleefstra Syndrome

Diseases in the Kleefstra Syndrome family:

Kleefstra Syndrome 1 Kleefstra Syndrome 2
Kleefstra Syndrome Due to a Point Mutation

Diseases related to Kleefstra Syndrome via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 53)
# Related Disease Score Top Affiliating Genes
1 kleefstra syndrome due to a point mutation 33.1 KMT2C EHMT1
2 kleefstra syndrome 1 32.3 PAEP NR1I3 KMT2C EHMT1
3 alacrima, achalasia, and mental retardation syndrome 30.3 KMT2C EHMT1
4 hypoplastic left heart syndrome 29.6 NOTCH1 EHMT1
5 kleefstra syndrome 2 12.7
6 hypotonia 10.6
7 autism spectrum disorder 10.4
8 autism 10.3
9 hypertelorism 10.2
10 epicanthus 10.2
11 neural tube defects 10.2
12 branchiootic syndrome 1 10.2
13 neuroblastoma 10.2
14 exophthalmos 10.2
15 hypopituitarism 10.2
16 microtia 10.2
17 angelman syndrome 10.2
18 macroglossia 10.2
19 down syndrome 10.2
20 pulmonary hypertension 10.2
21 microcephaly 10.2
22 chromosomal triplication 10.1
23 chromosome 9q duplication 10.1
24 papillomatosis, confluent and reticulated 10.1
25 gilles de la tourette syndrome 10.0
26 obsessive-compulsive disorder 10.0
27 polydactyly, postaxial, type a1 10.0
28 smith-magenis syndrome 10.0
29 cryptorchidism, unilateral or bilateral 10.0
30 abnormal hair, joint laxity, and developmental delay 10.0
31 deafness, autosomal recessive 4, with enlarged vestibular aqueduct 10.0
32 polydactyly 10.0
33 valproate embryopathy 10.0
34 koolen-de vries syndrome 10.0
35 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 10.0
36 apraxia 10.0
37 hypogonadotropic hypogonadism 10.0
38 hypospadias 10.0
39 expressive language disorder 10.0
40 hypogonadism 10.0
41 dysostosis 10.0
42 movement disease 10.0
43 sleep disorder 10.0
44 hypogonadotropism 10.0
45 lung disease 10.0
46 childhood apraxia of speech 10.0
47 ring chromosome 9 10.0
48 developmental dyspraxia 10.0
49 febrile seizures 10.0
50 ring chromosome 10.0

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



Diseases related to Kleefstra Syndrome

Symptoms & Phenotypes for Kleefstra Syndrome

Human phenotypes related to Kleefstra Syndrome:

31 (show top 50) (show all 64)
# Description HPO Frequency HPO Source Accession
1 malar flattening 31 hallmark (90%) HP:0000272
2 hypertelorism 31 hallmark (90%) HP:0000316
3 muscular hypotonia 31 hallmark (90%) HP:0001252
4 coarse facial features 31 hallmark (90%) HP:0000280
5 global developmental delay 31 hallmark (90%) HP:0001263
6 delayed speech and language development 31 hallmark (90%) HP:0000750
7 short nose 31 hallmark (90%) HP:0003196
8 anteverted nares 31 hallmark (90%) HP:0000463
9 intellectual disability, severe 31 hallmark (90%) HP:0010864
10 tented upper lip vermilion 31 hallmark (90%) HP:0010804
11 everted lower lip vermilion 31 hallmark (90%) HP:0000232
12 exaggerated cupid's bow 31 hallmark (90%) HP:0002263
13 obesity 31 frequent (33%) HP:0001513
14 sleep disturbance 31 frequent (33%) HP:0002360
15 constipation 31 frequent (33%) HP:0002019
16 macroglossia 31 frequent (33%) HP:0000158
17 hearing impairment 31 frequent (33%) HP:0000365
18 chronic otitis media 31 frequent (33%) HP:0000389
19 mandibular prognathia 31 frequent (33%) HP:0000303
20 ventricular septal defect 31 frequent (33%) HP:0001629
21 microcephaly 31 frequent (33%) HP:0000252
22 brachycephaly 31 frequent (33%) HP:0000248
23 arrhythmia 31 frequent (33%) HP:0011675
24 highly arched eyebrow 31 frequent (33%) HP:0002553
25 bicuspid aortic valve 31 frequent (33%) HP:0001647
26 coarctation of aorta 31 frequent (33%) HP:0001680
27 broad forehead 31 frequent (33%) HP:0000337
28 upslanted palpebral fissure 31 frequent (33%) HP:0000582
29 synophrys 31 frequent (33%) HP:0000664
30 aggressive behavior 31 frequent (33%) HP:0000718
31 autistic behavior 31 frequent (33%) HP:0000729
32 thickened helices 31 frequent (33%) HP:0000391
33 self-mutilation 31 frequent (33%) HP:0000742
34 agenesis of corpus callosum 31 occasional (7.5%) HP:0001274
35 seizures 31 occasional (7.5%) HP:0001250
36 scoliosis 31 occasional (7.5%) HP:0002650
37 developmental regression 31 occasional (7.5%) HP:0002376
38 bowel incontinence 31 occasional (7.5%) HP:0002607
39 recurrent respiratory infections 31 occasional (7.5%) HP:0002205
40 short stature 31 occasional (7.5%) HP:0004322
41 cryptorchidism 31 occasional (7.5%) HP:0000028
42 renal cyst 31 occasional (7.5%) HP:0000107
43 cerebral cortical atrophy 31 occasional (7.5%) HP:0002120
44 gastroesophageal reflux 31 occasional (7.5%) HP:0002020
45 stereotypy 31 occasional (7.5%) HP:0000733
46 renal insufficiency 31 occasional (7.5%) HP:0000083
47 dyspnea 31 occasional (7.5%) HP:0002094
48 hernia 31 occasional (7.5%) HP:0100790
49 delayed eruption of teeth 31 occasional (7.5%) HP:0000684
50 limitation of joint mobility 31 occasional (7.5%) HP:0001376

UMLS symptoms related to Kleefstra Syndrome:


seizures

GenomeRNAi Phenotypes related to Kleefstra Syndrome according to GeneCards Suite gene sharing:

26
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Decreased shRNA abundance (Z-score < -2) GR00366-A-10 9.23 KMT2C
2 Decreased shRNA abundance (Z-score < -2) GR00366-A-139 9.23 NOTCH1
3 Decreased shRNA abundance (Z-score < -2) GR00366-A-165 9.23 KMT2C
4 Decreased shRNA abundance (Z-score < -2) GR00366-A-22 9.23 KMT2C
5 Decreased shRNA abundance (Z-score < -2) GR00366-A-28 9.23 KMT2C NOTCH1
6 Decreased shRNA abundance (Z-score < -2) GR00366-A-65 9.23 NOTCH1
7 Decreased shRNA abundance (Z-score < -2) GR00366-A-75 9.23 NOTCH1

Drugs & Therapeutics for Kleefstra Syndrome

Search Clinical Trials , NIH Clinical Center for Kleefstra Syndrome

Genetic Tests for Kleefstra Syndrome

Genetic tests related to Kleefstra Syndrome:

# Genetic test Affiliating Genes
1 Chromosome 9q Deletion Syndrome 29 EHMT1

Anatomical Context for Kleefstra Syndrome

MalaCards organs/tissues related to Kleefstra Syndrome:

40
Heart, Tongue, Eye, Brain, Testes, Bone, Lung

Publications for Kleefstra Syndrome

Articles related to Kleefstra Syndrome:

(show top 50) (show all 76)
# Title Authors PMID Year
1
First prenatal diagnosis of a 'pure' 9q34.3 deletion (Kleefstra syndrome): A case report and literature review. 61 24
29160022 2018
2
EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction. 61 24
29416845 2018
3
Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder. 61 24
29069077 2017
4
Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities. 61 24
28498556 2017
5
Sleep Disturbance as a Precursor of Severe Regression in Kleefstra Syndrome Suggests a Need for Firm and Rapid Pharmacological Treatment. 61 24
28622207 2017
6
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. 61 24
27651234 2016
7
A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. 61 24
23232695 2013
8
Update on Kleefstra Syndrome. 61 24
22670141 2012
9
Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. 61 24
21204793 2011
10
Prevalence and architecture of de novo mutations in developmental disorders. 24
28135719 2017
11
Behavioral phenotype in the 9q subtelomeric deletion syndrome: a report about two adult patients. 24
19642112 2010
12
Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. 24
19264732 2009
13
Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. 24
19293338 2009
14
The chromosome 9q subtelomere deletion syndrome. 24
17910072 2007
15
Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. 24
16826528 2006
16
Interstitial 2.2 Mb deletion at 9q34 in a patient with mental retardation but without classical features of the 9q subtelomeric deletion syndrome. 24
16470689 2006
17
The diverse functions of histone lysine methylation. 24
16261189 2005
18
Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. 24
15805155 2005
19
Deletion 9q34.3 syndrome: genotype-phenotype correlations and an extended deletion in a patient with features of Opitz C trigonocephaly. 24
15805160 2005
20
Subtelomeric deletions of chromosome 9q: a novel microdeletion syndrome. 24
15264279 2004
21
Syndromes of disordered chromatin remodeling. 24
12859401 2003
22
Cryptic terminal deletion of chromosome 9q34: a novel cause of syndromic obesity in childhood? 24
12676904 2003
23
Cryptic chromosome rearrangements detected by subtelomere assay in patients with mental retardation and dysmorphic features. 24
12515261 2002
24
Subtle chromosomal rearrangements in children with unexplained mental retardation. 24
10568569 1999
25
KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies. 61
31924266 2020
26
Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype. 61
31914384 2020
27
Otopathology in Kleefstra Syndrome: A Case Report. 61
31750954 2019
28
Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling. 61
31666522 2019
29
[Kleefstra syndrome 1 and ring chromosome 9 in a case]. 61
31400141 2019
30
9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression. 61
31209758 2019
31
Chromosomal microarray analysis in fetuses with an isolated congenital heart defect: A retrospective, nationwide, multicenter study in France. 61
30896039 2019
32
Histone 4 Lysine 20 Methylation: A Case for Neurodevelopmental Disease. 61
30832413 2019
33
Shone's complex in a patient with chromosome 9q34.3 deletion (Kleefstra syndrome). 61
30585561 2019
34
Fetal valproate syndrome as a phenocopy of Kleefstra syndrome. 61
30151876 2018
35
Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome. 61
30063093 2018
36
Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome. 61
29554304 2018
37
Biochemical validation of EHMT1 missense mutations in Kleefstra syndrome. 61
29459631 2018
38
New Insights into Kleefstra Syndrome: Report of Two Novel Cases with Previously Unreported Features and Literature Review. 61
30448833 2018
39
Hypogonadotropic Hypogonadism and Kleefstra Syndrome due to a Pathogenic Variant in the EHMT1 Gene: An Underrecognized Association. 61
30370152 2018
40
Kleefstra Syndrome: The First Case Report From Iran. 61
29228531 2017
41
Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation. 61
28645799 2017
42
Altered neurite morphology and cholinergic function of induced pluripotent stem cell-derived neurons from a patient with Kleefstra syndrome and autism. 61
28742076 2017
43
Increased first-trimester nuchal translucency associated with a dicentric chromosome and 9q34.3 microdeletion syndrome. 61
27966372 2017
44
A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation. 61
28361100 2017
45
A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. 61
28057753 2017
46
A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors. 61
28361099 2017
47
Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation. 61
28071689 2017
48
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. 61
27789404 2016
49
Euchromatin histone methyltransferase 1 regulates cortical neuronal network development. 61
27767173 2016
50
Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling. 61
27373831 2016

Variations for Kleefstra Syndrome

Copy number variations for Kleefstra Syndrome from CNVD:

7
# CNVD ID Chromosome 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
11.31 KMT2C EHMT1
2 10.78 NOTCH1 KMT2C
3 10.41 KMT2C EHMT1

GO Terms for Kleefstra Syndrome

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 9.33 NR1I3 NOTCH1 EHMT1
2 transcription initiation from RNA polymerase II promoter GO:0006367 9.26 NR1I3 NOTCH1
3 negative regulation of transcription, DNA-templated GO:0045892 9.13 NR1I3 NOTCH1 EHMT1
4 histone lysine methylation GO:0034968 8.62 KMT2C EHMT1

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

# Name GO ID Score Top Affiliating Genes
1 methyltransferase activity GO:0008168 8.96 KMT2C EHMT1
2 histone-lysine N-methyltransferase activity GO:0018024 8.62 KMT2C EHMT1

Sources for Kleefstra Syndrome

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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