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Kleefstra Syndrome

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

, MD, PhD, , BASc, and , PhD.

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

Initial Posting: .

Summary

Disease 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 microdeletion of 9q34.3 and 25% by intragenic EHMT1 mutation. The 9q34.3 microdeletion can be detected by whole-genome approaches or targeted approaches (fluorescence in situ hybridization [FISH], multiplex ligation-dependent probe amplification [MLPA]) that determine the copy number of sequences within the deleted region. Intragenic EHMT1 mutations (e.g., missense and frameshifts) can be detected by sequencing of the coding region.

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 program, special education program, 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, 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 a mutation of 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 who have had a child with a 9q34.3 microdeletion or an EHMT1 mutation 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

Clinical 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].

Features that should prompt consideration of this diagnosis 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

Testing

Cytogenetic testing. The 9q34.3 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Molecular Genetic Testing

Gene. EHMT1 is the only gene in which mutation is known to account for the majority of features in Kleefstra syndrome [Kleefstra et al 2006a, Kleefstra et al 2009].

The two causes of Kleefstra syndrome:

  • 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
  • Intragenic EHMT1 mutation, accounting for about 25% of Kleefstra syndrome

Clinical testing

  • Deletion/duplication analysis. The 9q34.3 microdeletion can be detected by any number of molecular methods that determine the copy number of sequences within the deleted region. Both whole-genome and targeted approaches can be applied (Table 1, footnote 4).
  • Genomic approach. Because of the complex clinical presentation of Kleefstra syndrome, the majority of affected individuals are identified by a genome-wide screen for deletions/duplications. Array-based comparative genomic hybridization (aCGH) or aGH (array-based non-comparative genomic hybridization) using BAC, oligonucleotide, or SNP genotyping arrays 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 targeted approach. Gene-targeted methods (e.g., fluorescence in situ hybridization [FISH], multiplex ligation-dependent probe amplification [MLPA]) can be used if the syndrome is suspected clinically or for confirming the deletion after genomic microarray analysis.

    Note: (1) Since 9q34.3 microdeletions could be interstitial or even intragenic, an extensive MLPA analysis comprising probes covering all EHMT1 exons is preferred. (2) FISH cannot size the deletion routinely. Most MLPA approaches can size intragenic deletions.
  • Sequence analysis. Sequencing of the entire coding region of EHMT1 detects intragenic disease-causing mutations such as missense and frameshifts.

Table 1. Summary of Molecular Genetic Testing Used in Kleefstra Syndrome

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
EHMT1Deletion/duplication analysis 4 (genomic approach) Deletion of 9q34.3 (de novo terminal deletions, complex rearrangements or derivative chromosomes, interstitial deletion) ~75%
Deletion/duplication analysis 4 (EHMT1 targeted approach)Intragenic EHMT1 deletions and smaller contiguous gene deletions involving EHMT1
Sequence analysisSequence variants 5~25%

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

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Interpretation of test results

  • Deletion analysis. Depending on the initial test that identifies the 9q34.3 microdeletion, validation of the deletion by an independent method may be warranted.

    Note: If high-density genomic microarray platforms have been used for the identification of the microdeletion, validation of the deletion may not be necessary, as it is unlikely that more than 50-100 adjacent targets show an abnormal copy number by chance.
  • Sequence analysis.

Testing Strategy

To establish the diagnosis in a proband requires detection of a 9q34.3 microdeletion with involvement of at least part of EHMT1 or detection of an intragenic EHMT1 mutation.

  • Most microdeletions are detected by genomic microarray analysis performed as part of the evaluation of developmental delay or intellectual disability.
  • If Kleefstra syndrome is suspected based on the clinical features, a targeted technique to identify an EHMT1 microdeletion (e.g., FISH or MLPA) can be employed.
  • If a deletion is not found by either of the above two test methods, EHMT1 sequence analysis is recommended.

Note: The 9q34.3 microdeletion cannot be identified by routine chromosome analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the 9q34.3 microdeletion or EHMT1 mutation in the proband and/or of balanced carrier status in a parent.

Clinical Description

Natural History

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].

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

Figure 1

Figure

Figure 1. Photographs of patients showing the characteristic facial profile comprising brachycephaly, hypertelorism, synophrys/arched eyebrows, midface hypoplasia, protruding tongue, eversion of lower lip, and prognathism of chin. Five patients (AB), (more...)

Figure 2

Figure

Figure 2. Photographs of patients showing the characteristic facial profile comprising brachycephaly, hypertelorism, synophrys/arched eyebrows, midface hypoplasia, protruding tongue, eversion of lower lip, and prognathism of chin. Three different patients (more...)

With age, the facial appearance becomes coarser, with persisting midfacial hypoplasia 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 making sign languages or use of pictograms valuable 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 awakening – 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

Data collected so far indicate that individuals with an intragenic EHMT1 mutation (e.g., missense, nonsense) and those with a 9q34.3 microdeletion have similar clinical findings; however, the pulmonary infections and aspiration difficulties appear to be more severe in individuals with larger 9q34 deletions (≥3 Mb) than in those with smaller deletions or EHMT1 defects 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 identifications of additional individuals with intragenic EHMT1 defects led OMIM to assign the name Kleefstra to the syndrome.

Prevalence

No reliable figures are available yet on the prevalence of Kleefstra syndrome since affected individuals have only been identified in the last five to ten years as a result of improved techniques for deletion detection and after the more recent discovery of the causal role of mutation of EHMT1.

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

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 a mutation of EHMT1, 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 two 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].

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, two individuals diagnosed with a mosaic 9q34.3 microdeletion have been known to reproduce.
  • 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 Mutation

EHMT1 mutation in all cases to date has been de novo.

Parents of a proband

  • To date, no parents of an individual with an EHMT1 mutation have also had the mutation; all the disease-causing EHMT1 mutations have occurred de novo. All individuals are simplex cases (i.e., a single occurrence in the family).
  • When the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, germline mosaicism in a parent is also a possibility. To date no instances of germline mosaicism have been reported.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing for the specific EHMT1 mutation 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 mutation that also includes the germline, the risk to sibs is increased.

Offspring of a proband

  • No individual with an EHMT1 mutation has been known to reproduce.
  • Individuals who have an EHMT1 mutation would be expected to have a 50% chance of transmitting the mutation 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing may be offered to unaffected parents who have had a child with a 9q34.3 microdeletion or an EHMT1 mutation 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 Molecular Genetic Testing.
  • Intragenic EHMT1 mutation. 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 analyzed using DNA sequence analyses of the EHMT1 mutation in the manner described in Molecular Genetic Testing.

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 the unaffected parents of a child with Kleefstra syndrome if one of the parents has a balanced translocation involving the 9q34.3 region or mosaicism for a 9q34.3 microdeletion. PGD may also be an option for the parents of a child with Kleefstra syndrome who has an EHMT1 mutation, given that one parent could have germline mosaicism.

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
    PO Box 2189
    Caterham Surrey CR3 5GN
    United Kingdom
    Phone: +44 (0) 1883 330766
    Fax: +44 (0) 1883 330766
    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

Normal allelic variants. 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.

All normal variants reported to date are listed in Table 2 [Kleefstra et al 2006a]. Note: The nomenclature has been adjusted for the ‘updated’ NM_024757.4 sequence.

Pathogenic allelic variants. EHMT1 sequence variants include nonsense, splice site, and missense mutations. All intragenic EHMT1 mutations reported to date are listed in Table 2 [Kleefstra et al 2006a, Kleefstra et al 2009]. Note: The nomenclature has been adjusted for the ‘updated’ NM_024757.4 sequence.

Table 2. Selected EHMT1 Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change 1Reference Sequences
Normalc.444T>Cp.=NM_024757​.4
NP_079033​.4
c.1044G>Ap.=
c.1089T>Cp.=
c.1368C>Tp.=
c.1806G>Ap.=
Pathogenicc.871C>Tp.Arg291Ter
c.1413_1425delp.Pro473fs
c.1533_1536delp.Asp512fs
c.1810C>Tp.Gln604Ter
c.1858C>Tp.Arg620Ter
c.2029insGp.Pro677fs
c.2193-1G>Cp.?
c.2863_2864delp.Val955ArgfsTer221
c.2868-1G>Ap.?
c.2877_2880delp.Ser960GlyfsTer7
c.3181-80_3233delp.Tyr1061fs
c.3180+1G>Tp.?
c.3229C>Tp.Gln1077Ter
c.3218G>Ap.Cys1073Tyr
c.3502C>Tp.Arg1168Ter
c.3589C>Tp.Arg1197Trp

Note on variant classification: Variants listed in the table have been provided by the author(s). 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.

1. p.= designates that protein has not been analyzed, but no change is expected.

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

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 mutations that have been described disrupt the open reading frame of EHMT1 and are predicted to lead to nonsense-mediated decay (NMD). The one missense change 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 [Ausio 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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  14. Yatsenko SA, Cheung SW, Scott DA, Nowaczyk MJ, Tarnopolsky M, Naidu S, Bibat G, Patel A, Leroy JG, Scaglia F. et al. Deletion 9q34.3 syndrome: genotype-phenotype correlations and an extended deletion in a patient with features of Opitz C trigonocephaly. J Med Genet. 2005;42:328–35. [PMC free article: PMC1736036] [PubMed: 15805160]

Chapter Notes

Revision History

  • 5 October 2010 (me) Review posted live
  • 28 May 2010 (tk) Original submission
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