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Kleefstra Syndrome

Synonyms: 9q Subtelomeric Deletion Syndrome, 9q34.3 Microdeletion Syndrome, 9qSTDS

, MD, PhD, , BSc, and , PhD.

Author Information
, MD, PhD
Department of Human Genetics
Radboud University Medical Center
Nijmegen, The Netherlands
, BSc
Department of Human Genetics
Radboud University Medical Center
Nijmegen, The Netherlands
, PhD
Department of Human Genetics
Radboud University Medical Center
Nijmegen, The Netherlands

Initial Posting: ; Last Update: May 7, 2015.

Summary

Clinical characteristics.

Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate to severe spectrum of intellectual disability although a few individuals have mild delay and total IQ around 70. Although most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed including heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy/febrile seizures, autistic-like features in childhood, and extreme apathy or catatonic-like features after puberty.

Diagnosis/testing.

About 75% of Kleefstra syndrome is caused by a heterozygous microdeletion at chromosome 9q34.3 that includes at least part of EHMT1, and about 25% by a heterozygous intragenic EHMT1 pathogenic variant.

Management.

Treatment of manifestations: Ongoing routine care by a multidisciplinary team specializing in the care of children or adults with intellectual disability. Referral to age-appropriate early-childhood intervention programs, special education programs, or vocational training; speech/language therapy, physical and occupational therapy, and sensory integration therapy; specialized care for those with extreme behavior problems, movement disorders, sleep disorders, and/or epilepsy; standard treatment for cardiac, renal, urologic, hearing loss, and other medical issues.

Surveillance: Monitoring as needed of cardiac and renal/urologic abnormalities.

Genetic counseling.

Kleefstra syndrome, caused by a microdeletion at 9q34.3 or pathogenic variants in EHMT1, is inherited in an autosomal dominant manner. Almost all cases reported to date have been de novo; rarely, recurrence in a family has been reported when a parent has a balanced translocation involving the 9q34.3 region or somatic mosaicism for an interstitial 9q34.3 microdeletion. Except for individuals with somatic mosaicism for a 9q34.3 microdeletion, no individuals with Kleefstra syndrome have been known to reproduce. Prenatal testing may be offered to unaffected parents of a child with a 9q34.3 microdeletion or an EHMT1 pathogenic variant because of the increased risk of recurrence associated with the possibility of germline mosaicism, somatic mosaicism including the germline, or a balanced chromosome translocation.

Diagnosis

Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. A complex pattern of other findings can also be observed [Dawson et al 2002, Cormier-Daire et al 2003, Stewart et al 2004, Kleefstra et al 2005, Yatsenko et al 2005, Kleefstra et al 2006a, Kleefstra et al 2006b, Stewart & Kleefstra 2007, Kleefstra et al 2009, Yatsenko et al 2009].

Suggestive Findings

Features that should prompt consideration of Kleefstra syndrome include:

  • Intellectual disability, usually moderate to severe and associated with severe speech delay
  • Distinctive facial features
  • Childhood hypotonia
  • Motor delay
  • Heart defects
  • Renal/urologic defects
  • Genital defects (males)
  • Severe infections (respiratory)
  • Epilepsy/febrile seizures
  • Autistic-like features in childhood
  • Extreme apathy or catatonic(-like) features postpubertally
  • Structural brain abnormalities
  • White matter abnormalities

Establishing the Diagnosis

Establishing the diagnosis of Kleefstra syndrome in a proband requires detection of a 9q34.3 microdeletion with involvement of at least part of EHMT1 or detection of an EHMT1 pathogenic variant (Table 1) [Kleefstra et al 2006a, Kleefstra et al 2009]. EHMT1 inactivation accounts for the majority of features in Kleefstra syndrome.

Kleefstra syndrome is caused by one of two mechanisms:

  • Microdeletion of 9q34.3, accounting for about 75% of Kleefstra syndrome. In 28 unrelated individuals with a 9q34.3 microdeletion, three distinct categories were identified [Yatsenko et al 2009]:
    • 50% bona fide de novo terminal deletions
    • 25% interstitial deletions
    • 25% complex rearrangements or derivative chromosomes
  • An EHMT1 pathogenic variant, accounting for about 25% of Kleefstra syndrome.

Molecular testing approaches can include a genomic approach, EHMT1 gene-targeted deletion/duplication analysis and EHMT1 sequence analysis.

Genomic approach. Because of the complex clinical presentation of Kleefstra syndrome, the majority (~70%) of affected individuals are identified by a genome-wide screen for deletions/duplications. Chromosome microarray analysis (CMA) can detect the deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 9q34.3 region.

EHMT1 gene-targeted deletion/duplication analysis. Approximately 5% of individuals with Kleefstra syndrome have an intragenic deletion detectable by an assay designed to detect single-exon deletions or duplications (e.g., multiplex ligation-dependent probe amplification [MLPA], qPCR, and gene-targeted CMA). Deletions that are not intragenic but too small to be detected by CMA (e.g., containing the last part of C90RF37 and the first exon of EHMT1) require such gene-targeted methods designed for this region for detection.

Note: (1) FISH cannot size the deletion routinely. (2) The 9q34.3 microdeletion cannot be identified by routine chromosome analysis.

EHMT1 sequence analysis. Sequence analysis of the EHMT1 coding region detects a pathogenic variant in approximately 25% of probands.

Table 1.

Summary of Molecular Genetic Testing Used in Kleefstra Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by this Method
EHMT1Deletion/duplication analysis 3 (genomic approach)~70%
Gene-targeted deletion/duplication analysis 4 ~5%
Sequence analysis 5~25%
1.

See Table A. Genes and Databases for chromosome locus and protein name.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Deletion/duplication analysis (genomic approach) detects deletion of 9q34.3 (de novo terminal deletions, complex rearrangements or derivative chromosomes, interstitial deletion) using a chromosomal microarray (CMA) that includes this gene/chromosome segment.

4.

Gene-targeted deletion/duplication analysis detects intragenic EHMT1 deletions or duplications. Examples of methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single exon deletions or duplications.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Clinical Characteristics

Clinical Description

Kleefstra syndrome has a clinically recognizable phenotype that includes physical, developmental, and behavioral features. Males and females are affected equally [Stewart et al 2004, Yatsenko et al 2005, Kleefstra et al 2006b, Stewart & Kleefstra 2007, Kleefstra et al 2009, Willemsen et al 2012].

Birth weight is usually within the normal or above-normal range; in childhood, weight increases leading to obesity (50%) [Cormier-Daire et al 2003, Kleefstra et al 2009, Willemsen et al 2012]. The facial appearance is characterized by a brachy(-micro)cephaly, broad forehead, synophrys, unusual shape of eyebrows (arched or straight), mildly upslanted palpebral fissures, midface retrusion, thickened ear helices, short nose with anteverted nares, fleshy everted vermillion of the lower lip and exaggerated cupid’s bow or "tented" appearance of the vermillion of the upper lip, and protruding tongue and relative prognathism (Figure 1, Figure 2).

Figure 1. . Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midfaceretrusion, protruding tongue, eversion of the vermillion of the lower lip, and prognathism of chin.

Figure 1.

Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midfaceretrusion, protruding tongue, eversion of the vermillion of the lower lip, and prognathism of (more...)

Figure 2. . Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermillion of the lower lip, and prognathism of the chin.

Figure 2.

Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermillion of the lower lip, and prognathism of (more...)

With age, the facial appearance becomes coarser, with persisting midface retrusion and prognathism. An increased frequency of dental anomalies, specifically neonatal teeth and retention of primary dentition, has been observed.

Individuals with Kleefstra syndrome exhibit a range of cognitive and adaptive functioning, with the majority of individuals functioning in the moderate to severe spectrum of intellectual disability, although few individuals with only mild delay and total IQ (TIQ) around 70 are known. Most affected individuals have severe expressive speech delay with hardly any speech development, whereas general language development is usually at a higher level; thus, sign language or use of pictograms is of value to many affected individuals.

Motor development is impaired by childhood hypotonia, but almost all individuals achieve independent walking after age two to three years.

In a significant number of individuals with Kleefstra syndrome, congenital defects are observed. In 50% of individuals a (conotruncal) heart defect is present. Abnormalities that have been reported are ASD/VSD, tetralogy of Fallot, aortic coarctation, bicuspid aortic valve, and pulmonic stenosis. In a number of individuals atrial flutter has been reported.

Renal defects are seen in 10%-30% of cases and comprise vesico-ureteral reflux (VUR), hydronephrosis, renal cysts, and chronic renal insufficiency. Genital defects such as hypospadias, cryptorchidism, and small penis are reported in 30% of males

Several affected individuals have had talipes equinovarus. Other abnormalities that have been observed are epigastric hernia, tracheo-/bronchomalacia with respiratory insufficiency, and gastroesophageal reflux.

Seizures reported in 30% can include tonic-clonic seizures, absence seizures, and complex partial epilepsy.

Besides issues with social behavior, the behavioral phenotype includes sleep disturbances, stereotypies, mild self-injurious behaviors, and autism spectrum disorder usually recognized in early childhood. A few reports of adolescents and adults revealed progressive extreme apathy and catatonic(-like) behavior [Verhoeven et al 2010]. Sleep disturbance is characterized by frequent nocturnal and early morning awakenings as well as excessive daytime wakefulness – in contrast to the sleep disturbance observed in Smith Magenis syndrome.

Longitudinal data are insufficient to determine life expectancy; however, it should be noted that death in infancy or childhood can occur from complications such as heart defects and recurrent aspiration and pulmonary infections [Stewart & Kleefstra 2007].

Genotype-Phenotype Correlations

Current data indicate that individuals with an intragenic EHMT1 pathogenic variant (e.g., a missense or nonsense mutation) and those with a small (<1 Mb) 9q34.3 microdeletion have similar clinical findings. Individuals with larger deletions (≥1 Mb), however, have more somatic problems. Pulmonary infections and aspiration difficulties in particular appear to be more severe in individuals with larger 9q34 deletions than in those with smaller deletions or EHMT1 mutations only.

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.

Nomenclature

The disorder was first recognized following widespread subtelomeric FISH studies [Knight et al 1999, Dawson et al 2002]. After the identification of an individual with a similar phenotype and a de novo balanced translocation disrupting EHMT1, it was hypothesized that haploinsufficiency of this gene caused the phenotype present in individuals with a 9q34 deletion [Kleefstra et al 2005]. Subsequent identification of additional individuals with intragenic EHMT1 defects led OMIM to assign the name Kleefstra to the syndrome.

Prevalence

Reliable figures on penetrance are not yet available. Based on data from other rare disorders involving intellectual disability, Kleefstra syndrome is estimated to affect at least 1:200,000 individuals; as many individuals with this condition are not diagnosed, the true prevalence may be much higher.

The syndrome has been identified worldwide and in all ethnic groups.

Differential Diagnosis

Disorders in the differential diagnosis of Kleefstra syndrome:

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with the Kleefstra syndrome, the following evaluations are recommended following the initial diagnosis:

  • Complete review of systems
  • Physical and neurologic examination
  • Renal ultrasound examination to evaluate for possible renal/urologic anomalies
  • Echocardiogram and ECG to evaluate for possible structural cardiac anomalies and atrial rhythm defects; follow-up depending on the severity of any cardiac anomaly identified
  • Speech/language evaluation including audiologic examination
  • Assessment for signs and symptoms of gastroesophageal reflux (GER)
  • Physical and/or occupational therapy assessment
  • Sleep history
  • EEG if seizures are suspected
  • Neuroimaging (MRI) especially in the presence of findings such as seizures and/or movement disorder, extreme apathy/catatonia, and/or regression in psychomotor development
  • Medical genetics consultation

Treatment of Manifestations

The following are indicated:

  • Ongoing routine pediatric care by a pediatrician or neurologist, psychiatrist, and/or (for adults) specialist in the care of adults with intellectual disability
  • Depending on the age of the affected individual, referral to an early childhood intervention program, ongoing special education programs, and/or vocational training
  • Speech/language therapy, physical and occupational therapy, and sensory integration therapy
  • Specialized neurologic and psychiatric care for individuals with extreme behavior problems and/or movement disorder. Behavioral therapies include special education techniques that may help minimize behavioral outbursts in the school setting by emphasizing individualized instruction, structure, and a set daily routine.
  • Therapeutic management of the sleep disorder. No well-controlled treatment trials have been reported
  • Specialized neurologic care for individuals with epilepsy; management of seizures in accordance with standard practice
  • Standard treatment for cardiac, renal, urologic, and other medical issues
  • Auditory amplification if hearing loss is identified

Surveillance

Cardiac and renal/urologic abnormalities should be monitored as needed.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Kleefstra syndrome, caused by a microdeletion at 9q34.3 or an intragenic EHMT1 pathogenic variant, is inherited in an autosomal dominant manner; almost all cases reported to date have been de novo.

Risk to Family Members — 9q34.3 Microdeletion

9q34.3 microdeletion is usually de novo but may be inherited as the result of a complex chromosomal rearrangement or mosaicism in a parent.

Parents of a proband

  • To date, no parent-to-child transmission of an unbalanced derivative chromosome involving the 9q34.3 region has been observed.
  • Recurrence in families with a parent having a balanced translocation involving the 9q34.3 region has been described [Knight et al 1999, Dawson et al 2002].
  • To date, all interstitial 9q34.3 microdeletions detected are de novo, except for three families in which one of the parents was shown to have a somatic mosaic deletion. One family comprised a parent with learning difficulties who had two severely affected children with Kleefstra syndrome; the other family also comprised a parent with learning difficulties who had one affected child with Kleefstra syndrome [Author, personal observation].
  • Recommendations for the evaluation of asymptomatic parents of a proband with a 9q34.3 microdeletion include routine karyotyping with additional FISH analysis to determine if a balanced chromosomal rearrangement involving the 9q34.3 region is present.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • In the (unlikely) event that a parent has either germline mosaicism for a 9q34.3 microdeletion, low-level somatic mosaicism that includes the germline, or a balanced structural chromosome rearrangement involving the 9q34.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.

Offspring of a proband

  • To date, five individuals diagnosed with a mosaic 9q34.3 microdeletion have been known to reproduce [Willemsen et al 2011; T Kleefstra, personal communication].
  • Individuals who have the 9q34.3 microdeletion would be expected to have a 50% chance of transmitting the deletion to each child.

Risk to Family Members — EHMT1 Pathogenic Variant

Mutation of EHMT1 in almost all cases to date has occurred de novo.

Parents of a proband

  • To date, only one parent of an individual with an EHMT1 pathogenic variant has also had the pathogenic variant, although it was a mosaic pathogenic variant in an unaffected parent [Rump et al 2013]; therefore, in the vast majority of cases EHMT1 mutation has been de novo. All individuals are simplex cases (i.e., a single occurrence in the family).
  • When the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, germline mosaicism in a parent is also a possibility [Rump et al 2013].
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include molecular genetic testing for the specific EHMT1 pathogenic variant identified in the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • In the (unlikely) event that a parent has germline mosaicism or low-level somatic mosaicism for an EHMT1 pathogenic variant that also includes the germline, the risk to sibs is increased.

Offspring of a proband

  • No individual with a non-mosaic EHMT1 pathogenic variant has been known to reproduce.
  • Individuals who have a non-mosaic EHMT1 pathogenic variant would be expected to have a 50% chance of transmitting the pathogenic variant to each child.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with Kleefstra syndrome.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing for at-risk pregnancies requires prior identification of the 9q34.3 microdeletion or an EHMT1 pathogenic variant in the proband and/or of balanced carrier status in a parent. Prenatal testing may be offered to unaffected parents who have had a child with a 9q34.3 microdeletion or an EHMT1 pathogenic variant because of the recurrence risk associated with the possibility of germline mosaicism, somatic mosaicism including the germline, or a balanced chromosome translocation.

  • 9q34.3 microdeletion. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using FISH or MLPA in the manner described in Diagnosis, Establishing the Diagnosis.
  • Intragenic EHMT1 pathogenic variant. DNA preparations from fetal cells obtained by CVS at approximately ten to 12 weeks' gestation (or amniocentesis usually performed at approximately 15 to 18 weeks' gestation) can be tested for the EHMT1 pathogenic variant identified in the proband.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families at increased risk for a pregnancy with the 9q34.3 microdeletion or an EHMT1 pathogenic variant.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Chromosome Disorder Outreach (CDO)
    PO Box 724
    Boca Raton FL 33429-0724
    Phone: 561-395-4252 (Family Helpline)
    Email: info@chromodisorder.org
  • Unique: The Rare Chromosome Disorder Support Group
    G1 The Stables
    Station Road West
    Oxted Surrey RH8 9EE
    United Kingdom
    Phone: +44 (0) 1883 723356
    Email: info@rarechromo.org; rarechromo@aol.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Kleefstra Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Kleefstra Syndrome (View All in OMIM)

607001EUCHROMATIC HISTONE METHYLTRANSFERASE 1; EHMT1
610253KLEEFSTRA SYNDROME

Gene structure. The previously defined EHMT1 transcript (NM_024757.3) contained 26 exons, the translation start site being located in exon 2. The 'updated' NM_024757.4 version varies significantly, and contains an extra 5' exon. The novel open reading frame comprises 27 coding exons. The translation start site is located in the "novel" exon 1, 97.6 kb proximal to the ‘old’ ATG start codon. Diagnostic testing so far has been directed towards the 25 coding exons of the EHMT1 NM_024757.3 sequence. Since three individuals with Kleefstra syndrome harbor interstitial 9q microdeletions encompassing only this novel EHMT1 sequence in addition to several proximally located genes [Author, personal observation], routine diagnostic testing should be adjusted to the novel transcript. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. EHMT1 sequence variants include nonsense, splice site, and missense mutations and small deletions and duplications (Table 2) [Kleefstra et al 2006a, Kleefstra et al 2009, Willemsen et al 2012]. Note: The nomenclature has been adjusted for the ‘updated’ NM_024757.4 sequence.

Table 2.

Selected Pathogenic EHMT1 Allelic Variants

DNA Nucleotide Change
(Alias) 1
Protein Amino Acid ChangeReference Sequences
c.871C>Tp.Arg291TerNM_024757​.4
NP_079033​.4
c.1413_1425delp.Pro473GlnfsTer86
c.1533_1536delp.Asp512AlafsTer50
c.1810C>Tp.Gln604Ter
c.1858C>Tp.Arg620Ter
c.2028dupp.Pro677AlafsTer21
c.2193-1G>Cp.?
c.2863_2864delGTp.Val955ArgfsTer221
c.2868-1G>Ar.spl?
c.2877_2880delTTCT (2878_2881del) p.Ser960GlyfsTer7
c.3181-80_3233delr.spl? 2
c.3180+1G>Tr.spl?
c.3218G>Ap.Cys1073Tyr
c.3229C>Tp.Gln1077Ter
c.3502C>Tp.Arg1168Ter
c.3589C>Tp.Arg1197Trp

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

p.? indicates that a protein has not been analyzed; an effect is expected but difficult to predict.

r.spl? designates a change expected to affect splicing.

1.

Variant designation that does not conform to current naming conventions

2.

Donor splice site

Normal gene product. The NM_024757.4 transcript encodes a protein of 1298 amino acid residues. EHMT1 encodes euchromatin histone-lysine N-methyl transferase 1, a protein involved in histone methylation. DNA is wrapped around histones, and histone tails have an important role in folding of chromatin fibers. Methylation of these histone tails is thought to regulate this folding process, hereby altering the accessibility of DNA to proteins mediating transcription [Martin & Zhang 2005]. The restricted expression of EHMT1 in the mouse brain (olfactory bulb, the anterior/ventral ventricular wall, hippocampus, and piriform cortex) supports a role of epigenetic histone modification in normal brain development [Kleefstra et al 2005].

Abnormal gene product. Haploinsufficiency resulting from deletion or inactivation of one EHMT1 allele is the cause of Kleefstra syndrome. The majority of pathogenic variants disrupt the open reading frame of EHMT1 and are predicted to lead to nonsense-mediated decay. The one missense mutation described to date is predicted to have an influence on the local conformation of the pre-SET domain of the EHMT1 protein, thereby reflecting a null allele [Kleefstra et al 2009]. Besides EHMT1, other genes associated with intellectual disability (e.g., MECP2, RSK2, and XNP) appear to play a role in chromatin remodeling [Ausió et al 2003]. Loss of proper regulation of chromatin structure can result in deregulation of gene transcription and inappropriate protein expression. This can in turn contribute to complex genetic disorders including intellectual disability.

References

Literature Cited

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  15. Willemsen MH, Vulto-van Silfhout AT, Nillesen WM, Wissink-Lindhout WM, van Bokhoven H, Philip N, Berry-Kravis EM, Kini U, van Ravenswaaij-Arts CM, Delle Chiaie B, Innes AM, Houge G, Kosonen T, Cremer K, Fannemel M, Stray-Pedersen A, Reardon W, Ignatius J, Lachlan K, Mircher C, Helderman van den Enden PT, Mastebroek M, Cohn-Hokke PE, Yntema HG, Drunat S. Kleefstra. Update on Kleefstra Syndrome: Mol Syndromol. 2012;2:202–12. [PMC free article: PMC3366700] [PubMed: 22670141]
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Chapter Notes

Revision History

  • 7 May 2015 (me) Comprehensive update posted live
  • 5 October 2010 (me) Review posted live
  • 28 May 2010 (tk) Original submission
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