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Rubinstein-Taybi Syndrome

Synonym: Broad Thumbs-Hallux Syndrome
, MD
Director, Medical Genetics
Professor, Pediatrics
University of Tennessee College of Medicine
Chattanooga, Tennessee

Initial Posting: ; Last Revision: August 20, 2009.

Summary

Disease characteristics. Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and great toes, short stature, and moderate to severe intellectual disability. The characteristic craniofacial features are downslanting palpebral fissures, columella extending below the nares, highly arched palate, grimacing smile, and talon cusps. Prenatal growth is often normal; however, height, weight, and head circumference percentiles rapidly drop in the first few months of life. Obesity may occur in childhood or adolescence. IQ scores range from 25 to 79; average IQ is between 36 and 51. Other variable findings are coloboma, cataract, congenital heart defects, renal abnormalities, and cryptorchidism.

Diagnosis/testing. The diagnosis of RSTS is primarily based on clinical features. Chromosome abnormalities are occasionally observed on routine cytogenetic testing. CREBBP and EP300 are the only genes currently known to be associated with RSTS. FISH analysis of CREBBP detects microdeletions in approximately 10% of individuals with RSTS. Sequence analysis detects CREBBP mutations in another 30%-50% of affected individuals. Mutations in EP300 are identified in approximately 3% of individuals with RSTS.

Management. Treatment of manifestations: Early intervention programs, special education, vocational training to address developmental disabilities, and referral to behavioral specialists/psychologists and support groups/resources for family members; standard treatment for eye abnormalities, hearing loss, cardiac defects, cryptorchidism, and sleep apnea; surgical repair of significantly angulated thumbs or duplicated halluces; aggressive management of gastroesophageal reflux and constipation.

Surveillance: Monitoring of growth and feeding, especially in the first year of life; annual eye and hearing evaluations; and routine monitoring for cardiac, dental, and renal anomalies.

Genetic counseling. RSTS is inherited in an autosomal dominant manner. RSTS typically occurs as the result of a de novo mutation in the family; most individuals represent simplex cases (i.e., the only affected member in a family). In most instances, the parents of an individual with RSTS are not affected. When the parents are clinically unaffected, the empiric recurrence risk for sibs is approximately 0.1%. Individuals with RSTS rarely reproduce. The theoretical risk to offspring is 50%. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation or deletion in the family is known.

Diagnosis

Clinical Diagnosis

The diagnosis of Rubinstein-Taybi syndrome (RSTS) is established by clinical findings.

Craniofacial appearance (see Figure 1)

Figure 1

Figure

Figure 1. Typical facial appearance in RSTS. Note arched brows, downslanting palpebral fissures, nasal septum extending below alae nasi, and grimacing smile.

  • Downslanting palpebral fissures
  • Beaked nose with the columella extending below the nares
  • Highly arched palate
  • Grimacing smile
  • Talon cusps, an accessory cusp-like structure on the lingual side of the tooth, usually occurring on the maxillary incisors of the permanent dentition

Other features (see Figures 2, 3)

Figure 2

Figure

Figure 2. A. Broad terminal phalanges B. Broad, radially deviated thumbs

Figure 3

Figure

Figure 3. Broad, partially duplicated great toes

  • The thumbs and great toes are almost always broad and often angulated.
  • The distal phalanges of the fingers may appear broad.
  • The proximal phalanges may be abnormally shaped. Radiographs of the hands and feet in individuals with RSTS are unusual but not necessarily diagnostic.
  • Almost all males have undescended testes.
  • Structural abnormalities of the urinary tract are common.
  • Congenital heart defects of various types occur in approximately one third of individuals with RSTS.

Growth

  • While prenatal growth is often normal, height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood.
  • Obesity may occur in childhood or adolescence and short stature is typical in adulthood.

Intellectual disability. The average IQ ranges between 35 and 50; however, developmental outcome varies considerably. A few individuals have been reported with IQs in the 70s.

Molecular Genetic Testing

Genes. CREBBP and EP300 are the only genes currently known to be associated with Rubinstein-Taybi syndrome (RSTS) [Roelfsema et al 2005].

Clinical testing

CREBBP

  • Sequence analysis of all the exons and intron/exon boundaries. Detection frequency varies among laboratories from approximately 30% to 50% of RSTS cases.
  • FISH. Five cosmid probes (RT100, RT102, RT191, RT203, and RT166) spanning the 150 kb of CREBBP are available commercially. An inventory of all published RSTS microdeletions [Petrij et al 2000a, Petrij et al 2004] showed that the microdeletion frequency in RSTS is approximately 10% (using 1-5 cosmids, the detection rate was 38/391 [~10%]; using the complete set of five probes, the detection rate was 8/89 [~9%]). Ideally, the five cosmids should be used simultaneously to detect all submicroscopic deletions.
  • Deletion/duplication analysis describes a method(s) that can be used to detect small deletions or duplications within the gene that may not be detected by FISH or by sequence analysis of genomic DNA. Such deletions have been demonstrated in studies of CREBBP. Stef et al [2007] detected deletions in 17/83 of patients (20.5%) with typical features of RSTS using array CGH and quantitative multiplex fluorescent-PCR.

EP300

Table 1. Summary of Molecular Genetic Testing Used in Rubinstein-Taybi Syndrome

Gene SymbolProportion of RSTS Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Gene and Test Method 1
CREBBP>60%Sequence analysisSequence variants 230%-50%
FISH~10% 3
Deletion / duplication analysis 4Exonic, multiexonic, and whole-gene deletions10%-20% 5
EP3003%Sequence analysisSequence variants3% 5
Deletion/ duplication analysis 4Exonic, multiexonic, and whole-gene deletions

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

2. 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.

3. Petrij et al [2000a], Petrij et al [2004], Schorry et al [2008]

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. 10/53 patients were found to have a deletion or duplication not detected by FISH [Roelfsema et al 2005].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming the diagnosis in a proband

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Rubinstein-Taybi syndrome (RSTS) is frequently recognized at birth or in infancy because of the striking facial features and characteristic hand and foot findings. Problems in early life include respiratory difficulties, feeding problems, poor weight gain, recurrent infections, and severe constipation. Moderate intellectual disability is typical.

Eye. Eye findings include strabismus, refractory errors, ptosis, nasolacrimal duct obstruction, cataracts, coloboma, nystagmus, glaucoma, and corneal abnormalities. van Genderen et al [2000] demonstrated a high frequency of retinal dysfunction on ERG.

Cardiac. Approximately one third of affected individuals have a variety of congenital heart defects.

Genitourinary. Renal abnormalities are very common and almost all boys have undescended testes.

Orthopedic. Orthopedic issues include dislocated patellas, lax joints, spine curvatures, Legg-Perthes disease, slipped capital femoral epiphysis, and cervical vertebral abnormalities [Yamamoto et al 2005].

Sleep apnea. Obstructive sleep apnea syndrome is often a considerable problem and may be caused by the combination of a narrow palate, micrognathia, hypotonia, obesity, and easy collapsibility of the laryngeal walls.

Skin. Keloids may occur with only minimal trauma to the skin. Pilomatrixomas have been reported [Masuno et al 1998, Bayle et al 2004].

Dental. Dental problems include crowding of teeth, malocclusion, multiple caries, hypodontia, hyperdontia, natal teeth, and talon cusps on the upper incisors of the secondary dentition.

Tumors. Tumors reported in individuals with RSTS include meningioma, pilomatrixoma, rhabdomyosarcoma, pheochromocytoma, neuroblastoma, medulloblastoma, oligodendroglioma, leioyosarcoma, seminoma, odontoma, choristoma, and leukemia [Masuno et al 1998, Roelfsema & Peters 2007].

Growth. Although prenatal growth is usually normal, parameters for height, weight, and head circumference fall below the fifth percentile during infancy. Males often become overweight during childhood while females become overweight during adolescence. Average height for adult males is 153.1 cm and for adult females is 146.7 cm. Stevens et al [1990] published growth grids.

Puberty. Puberty and sexual development are normal.

Intellect. Delayed development is typical in children with RSTS. In one study, the average age of walking was 30 months, first words 25 months, and toilet training 62 months. Speech delay occurs in 90% of children and some remain largely nonverbal.

The average IQ in one study was 51 and in another study was 36. IQ scores range from 25 to 79. The performance IQ is usually higher than the verbal IQ.

Regression in skills is not typical for RSTS.

Behavior. Short attention span, decreased tolerance for noise and crowds, impulsivity, and moodiness are frequently observed. Schorry et al [2008] noted frequent autistic behaviors in their study of 93 affected individuals. Other abnormal behaviors included attention problems, hyperactivity, self-injurious behaviors, and aggressive behaviors. Stevens et al [1999] also noted frequent autistic behavior in RSTS.

Genotype-Phenotype Correlations

Schorry et al [2008] studied 93 individuals with RSTS and noted 52 with definitive CREBBP mutations. No significant differences were found in congenital anomalies, tumors, dysmorphic features, or level of intellectual impairment between those with and without mutations. Growth retardation tended to be greater in the group without mutations but this was not statistically significant. However, seizures were more common in those with CREBBP mutations. Individuals with large deletions trended toward more severe cognitive impairment and autistic behavior but this did not reach statistical significance.

Although several authors reported no phenotypic differences in individuals with and without 16p deletions encompassing CREBBP [Blough et al 2000, Petrij et al 2000a], Hennekam et al [1993] found an increased frequency of microcephaly, partial duplication of the hallux, and angulation of the first rays of the hands and feet in those with deletions. No difference in mental functioning was apparent.

Hou [2005] suggested that disease severity correlated with size of deletion including CREBBP. Bartsch et al [2006] reported three individuals with severe RSTS (including failure to thrive, life-threatening infections, and death in infancy) who had large deletions encompassing CREBBP and the contiguous genes DNASE1 and TRAP1. However, Gervasini et al [2007] and Stef et al [2007] reported affected individuals with deletions of similar scope who did not have a severe phenotype.

Mosaic microdeletions have been noted by Gervasini et al [2007] and Schorry et al [2008]; these individuals tended to have a less severe phenotype than those with non-mosaic deletions.

There are only a few reports of individuals with EP300 mutations [Bartholdi et al 2007, Zimmermann et al 2007]. The features in these persons are said to be milder, particularly the skeletal findings. Some have normal hands and feet. Mental development also seems to be better, with intelligence ranging from borderline normal to intellectual disability.

Prevalence

Hennekam et al [1990b] reported a birth prevalence of 1:100,000 to 1:125,000 for RSTS in the Netherlands.

The majority of individuals reported with RSTS are of European origin; however, some black and Asian individuals with RSTS have been seen. Whether the occurrence of RSTS is lower in non-white populations or the observed difference is the result of other factors is not known.

Differential Diagnosis

Given the distinctive facial features and hand and foot abnormalities, the diagnosis of Rubinstein-Taybi syndrome (RSTS) is usually straightforward.

Broad/angulated thumbs and great toes may be seen in the FGFR-related craniosynostosis syndromes (i.e., Pfeiffer syndrome and Apert syndromes), Saethre-Chotzen syndrome, and Greig cephalopolysyndactyly syndrome. The presence of craniosynostosis and the difference in facial features should differentiate these disorders.

The eight disorders considered as part of the FGFR-related craniosynostosis syndromes are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans, and Muenke syndrome (FGFR3-related isolated coronal synostosis). All but Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings; Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis. The diagnosis of Muenke syndrome (FGFR3-related coronal synostosis) is based on identification of a disease-causing mutation in FGFR3. The diagnosis of FGFR2-related isolated coronal synostosis is based on identification of a disease-causing mutation in FGFR2. The diagnosis of the other six FGFR-related craniosynostoses is based on clinical findings; however, molecular genetic testing of FGFR1, FGFR2, and FGFR3 may be helpful in establishing the diagnosis of these syndromes in questionable cases. FGFR-related craniosynostosis is inherited in an autosomal dominant manner.

Classic Saethre-Chotzen syndrome is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), ptosis, and characteristic appearance of the ear (small pinna with a prominent crus). Syndactyly of digits two and three of the hand is variably present. Although mild-to-moderate developmental delay and intellectual disability have been reported, normal intelligence is more common. Less common manifestations of Saethre-Chotzen syndrome include short stature, parietal foramina, vertebral fusions, radioulnar synostosis, cleft palate, maxillary hypoplasia, ocular hypertelorism, hallux valgus, duplicated distal hallucal phalanx, and congenital heart malformations. The diagnosis of Saethre-Chotzen syndrome is made primarily on clinical findings. Occasionally, affected individuals have a chromosome translocation involving 7p21 or ring chromosome 7. TWIST1 is the only gene known to be associated with Saethre-Chotzen syndrome. TWIST1 mutations are identified in 46%-80% of affected individuals using a combination of deletion/duplication analysis and sequence analysis (exon 1). Saethre-Chotzen syndrome is inherited in an autosomal dominant manner.

Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true ocular hypertelorism, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type 4 and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability. The diagnosis of GCPS is based on clinical findings and family history. Standard Giemsa-banding cytogenetic studies can detect translocations or gross cytogenetic deletions involving 7p13. FISH analysis detects deletions in the estimated 5%-10% of individuals with large deletions; comparative genomic hybridization array may become an alternative to FISH in the future. GLI3 is the only gene known to be associated with GCPS; GLI3 alterations (i.e., cytogenetic abnormalities involving GLI3 or mutations of GLI3) can be identified in more than 75% of typically affected individuals. It is inherited in an autosomal dominant manner.

Broad thumbs are seen in brachydactyly type D as an isolated finding. Unilateral or bilateral shortening of the distal phalanx of the thumb is present. Inheritance is autosomal dominant.

The facial features of Floating-Harbor syndrome can appear similar to RSTS in some individuals. This syndrome is characterized by short stature, triangular face, prominent nose, thin lips, short neck, and developmental delay. The hand and foot findings are distinct from those of RSTS.

Cotsirilos et al [1987] reported a mother and two children with RSTS-like facial and extremity features but with normal intelligence.

Keipert syndrome is characterized by broad thumbs and halluces but is distinguished by hearing loss and characteristic facial features.

Kargi et al [2001] reported an individual with hand and foot findings similar to those of RSTS who also had mild pterygia.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Rubinstein-Taybi syndrome (RSTS), the following evaluations are suggested [Wiley et al 2003]:

  • Measurement of growth and plotting of parameters on published syndrome-specific growth charts
  • Multidisciplinary developmental evaluation including assessment of gross and fine motor skills, speech/language, cognitive abilities, and vocational skills
  • Ophthalmologic examination
  • Hearing evaluation using auditory brain stem evoked response testing (see Deafness and Hereditary Hearing Loss Overview for details of evaluation)
  • Dental and orthodontic evaluations
  • Echocardiogram or evaluation by cardiologist for structural heart defects
  • Assessment for gastroesophageal reflux as warranted
  • Assessment for constipation
  • Renal ultrasound examination
  • Assessment for presence of cryptorchidism in males
  • Orthopedic assessment of thumbs and halluces, joints and spine
  • Evaluation of obstructive sleep apnea syndrome if indicated by snoring, particular sleeping posture, wakefulness at night, and excessive sleepiness during the daytime

Treatment of Manifestations

The following are appropriate:

  • Early intervention programs, special education, and vocational training to address developmental disabilities
  • Standard treatment for refractive errors, strabismus, glaucoma, cataracts, and other eye abnormalities if identified
  • Standard treatment for hearing loss if identified
  • Standard treatment for cardiac defects if identified
  • Aggressive management of gastroesophageal reflux and constipation
  • Standard treatment for cryptorchidism if identified
  • Surgical repair of significantly angulated thumbs or duplicated halluces
  • Appropriate treatment for sleep apnea if identified
  • Behavior management strategies including referral to a behavioral specialist/psychologist and consideration of medication if needed
  • Referral of the family to support groups and other resources

Prevention of Secondary Complications

Individuals with RSTS can be difficult to intubate because of the easy collapsibility of the laryngeal wall. An anesthesiologist comfortable with managing complex pediatric airway problems should therefore administer general anesthesia when needed. Because of these problems, individuals with RSTS may require earlier intubation and later extubation than other individuals undergoing similar procedures.

Surveillance

Surveillance includes the following:

  • Close monitoring of growth, especially in the first year of life
  • Annual follow-up evaluation for ophthalmologic abnormalities
  • Yearly audiologic screens; more frequent evaluation if a history of multiple episodes of otitis media exists
  • Monitoring as per routine for cardiac or renal anomalies
  • Regular dental and orthodontic follow-up

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

Rubinstein-Taybi syndrome (RSTS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • RSTS typically occurs as a de novo event in the family; most individuals are the only affected member of their families. The parents of most individuals with RSTS are not affected.
  • Recommendations for the evaluation of parents of a proband include clinical examination for physical findings associated with RSTS. In the absence of clinical findings of RSTS in the parents, laboratory testing of the parents is not indicated.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • When the parents are clinically unaffected, the empiric recurrence risk for sibs is approximately 0.1%.
  • If neither parent of the proband has a CREBBP mutation identified in the proband detectable in their DNA, it is presumed that the proband has a de novo gene mutation and the risk to the sibs of the proband depends on the probability of germline mosaicism.
  • Although no instances have been reported, germline mosaicism remains a possibility.

Offspring of a proband. Individuals with RSTS have rarely reproduced. The theoretical risk to offspring is 50%.

Other family members of a proband. The risk to other family members of a proband is typically not increased over that of the general population, as most individuals with RSTS do not have an affected parent.

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 are affected or at risk.

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

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 some families in which the disease-causing mutation has been identified.

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.

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. Rubinstein-Taybi 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 Rubinstein-Taybi Syndrome (View All in OMIM)

180849RUBINSTEIN-TAYBI SYNDROME 1; RSTS1
600140CREB-BINDING PROTEIN; CREBBP
602700E1A-BINDING PROTEIN, 300-KD; EP300
613684RUBINSTEIN-TAYBI SYNDROME 2; RSTS2

CREBBP

Normal allelic variants. The human CREBBP cDNA measures 10197 bp in length, of which 7329 bp are translated into 2442 amino acids (GenBank Accession No 85962). CREBBP is 154 kb in length, includes 31 transcribed exons [Petrij et al 2000a, Coupry et al 2002, Petrij et al 2004], and is transcriptionally oriented from centromere to telomere. Five cosmids (RT100, RT102, RT191, RT203, RT166) and a BAC clone (AC007151) span the entire human CREBBP [Blough et al 2000, Petrij et al 2000a, Coupry et al 2002].

Pathologic allelic variants. Evidence suggests that Rubinstein-Taybi syndrome (RSTS) is caused by haploinsufficiency of CREBBP product [Petrij et al 2001]. Microdeletions are seen in approximately 10% of individuals with RSTS [Taine et al 1998, Bartsch et al 1999, Petrij et al 2000a, Murata et al 2001]. Nonsense, missense, and splicing mutations are reported as well [Petrij et al 2000a, Murata et al 2001, Bartsch et al 2002, Coupry et al 2002]. Mutations in the HAT domain of CREBBP result in the inability to acetylate histones and reduced coactivator function for the transcription factor CREB [Kalkhoven et al 2003]. FISH and other deletion/duplication analytical techniques can detect up to about 20% of contiguous and intragenic deletions in CREBBP (see Molecular Genetic Testing).

Normal gene product. The CREB-binding protein (CREBBP), a 265-kd protein containing 2,442 amino acids, is involved in regulating the expression of many genes [Petrij et al 2001]. CREBBP provides a molecular bridge between transcription factors that bind to specific DNA sequences and the protein complex that is required for transcription. It is a mediator of different signaling pathways and can also act as a negative regulator of the cell cycle by repressing the transition from G1 to S phase [Petrij et al 2001]. CREBBP has histone acetyltransferase activity, which allows transcription factors access to DNA. It is highly expressed in essentially all tissue types [Petrij et al 2001].

Abnormal gene product. Germline mutations in CREBBP may lead to a truncated CREB-binding protein or one with an amino acid substitution. Mutations in the HAT domain interfere with the acetylation of histones, which is an important step in transcription activation. Somatic mutations in CREBBP may lead to cancer, as CREBBP also functions as a tumor suppressor.

EP300

Normal allelic variants. EP300 is 87.75 kb in length, including 31 exons. The length of the mRNA is 8761 bp, which are translated into 2414 amino acids.

Pathologic allelic variants. RSTS can be caused by mutations in EP300 [Roelfsema et al 2005]. Three of 92 individuals with RSTS studied by Roelfsema et al [2005] were found to have mutations in EP300. (For more information, see Table A.)

Mutations in EP300 may also lead to cancer, as the gene functions as a tumor suppressor.

Normal gene product. EP300 produces the protein p300, which shares 63% homology with CREBBP at the amino acid level [Iyer et al 2004]. The p300 protein also functions as a transcription cofactor for a number of nuclear proteins. It is a histone acetyltransferase and functions as a tumor suppressor [Iyer et al 2004].

Abnormal gene product. Mutations result in truncated p300 protein or absence of allele expression, which may lead to loss of HAT activity.

References

Literature Cited

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Chapter Notes

Revision History

  • 20 August 2009 (cd) Revision: sequence analysis, deletion/duplication analysis, and prenatal diagnosis available clinically for EP300 mutations
  • 16 April 2009 (me) Comprehensive update posted live
  • 26 June 2007 (cd) Revision: sequence analysis and mutation scanning available clinically
  • 2 October 2006 (me) Comprehensive update posted to live Web site
  • 20 December 2005 (cs) Revision: EP300 mutations found to cause some cases of RSTS
  • 13 September 2004 (cd) Revision: testing
  • 22 July 2004 (me) Comprehensive update posted to live Web site
  • 30 August 2002 (tk,me) Review posted to live Web site
  • 5 April 2002 (cs) Original submission
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