Human Gene Module / Chromosome 16 / CREBBP

CREBBPCREB binding protein

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
16 / 41
Rare Variants / Common Variants
113 / 5
EAGLE Score
31.35
Strong Learn More
Aliases
CREBBP, CBP,  KAT3A,  RSTS
Associated Syndromes
Rubinstein-Taybi syndrome, Menke-Hennekam syndrome 1, Tourette syndrome, Menke-Hennekam syndrome 1, DD, ID, Rubinstein-Taybi syndrome 1, DD, ID
Chromosome Band
16p13.3
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Relevance to Autism

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort (Barnby et al., 2005). This gene has also been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS).

Molecular Function

This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. First isolated as a nuclear protein that binds to cAMP-response element binding protein (CREB), this gene is now known to play critical roles in embryonic development, growth control, and homeostasis by coupling chromatin remodeling to transcription factor recognition. Mutations in this gene cause Rubinstein-Taybi syndrome (RTS). Chromosomal translocations involving this gene have been associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants encoding different isoforms.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CREBBP (41 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome Coupry I , et al. (2002) No ASD
2 Primary Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT Barnby G , et al. (2005) Yes -
3 Support Genotype-phenotype correlations in Rubinstein-Taybi syndrome Schorry EK , et al. (2008) No -
4 Support Socio-behavioral characteristics of children with Rubinstein-Taybi syndrome Galra C , et al. (2009) No -
5 Support Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinstein-Taybi syndrome Cal F , et al. (2013) No DD
6 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel Brett M , et al. (2014) Yes MCA
7 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
8 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
9 Support Whole exome sequencing for a patient with Rubinstein-Taybi syndrome reveals de novo variants besides an overt CREBBP mutation Yoo HJ , et al. (2015) No ASD, ID
10 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
11 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
12 Support CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein-Taybi syndrome Wincent J , et al. (2016) No -
13 Support CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype Menke LA , et al. (2016) No DD, ID, ASD or autistic features
14 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
15 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No DD
16 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder Willsey AJ , et al. (2017) No -
17 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No Epilepsy/seizures, macrocephaly
18 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
19 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) No -
20 Support Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome Menke LA , et al. (2018) No DD, ID, ASD or autistic behavior
21 Recent Recommendation Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma Merk DJ , et al. (2018) No -
22 Support Rubinstein-Taybi syndrome: New neuroradiological and neuropsychiatric insights from a multidisciplinary approach Ajmone PF , et al. (2018) No -
23 Support Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP Banka S , et al. (2019) No Autistic features
24 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No Stereotypies
25 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
26 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
27 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
28 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
29 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
30 Support - Mahjani B et al. (2021) Yes -
31 Support - Nishi E et al. (2021) No ASD, epilepsy/seizures
32 Support - Elalaoui SC et al. (2021) No -
33 Support - Brea-Fernández AJ et al. (2022) No -
34 Support - Zhou X et al. (2022) Yes -
35 Support - Kipkemoi P et al. (2023) No ID
36 Support - Sheth F et al. (2023) Yes DD, ID
37 Support - et al. () Yes -
38 Support - et al. () Yes -
39 Support - et al. () Yes -
40 Support - et al. () No -
41 Support Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP Petrij F , et al. (1995) No ASD
Rare Variants   (113)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 38438125 et al. ()
A>T - intron_variant - - - 12070251 Coupry I , et al. (2002)
C>G - intron_variant - - - 12070251 Coupry I , et al. (2002)
T>C - intron_variant - - - 12070251 Coupry I , et al. (2002)
- - copy_number_loss De novo - - 23315884 Cal F , et al. (2013)
- - copy_number_loss Unknown - - 26788536 Wincent J , et al. (2016)
- - copy_number_loss Unknown - - 31406558 Munnich A , et al. (2019)
C>T p.Arg413Ter stop_gained - - - 12070251 Coupry I , et al. (2002)
- - copy_number_loss De novo - - 34795756 Elalaoui SC et al. (2021)
c.3559C>T p.Gln1187Ter stop_gained Unknown - - 38003033 et al. ()
A>T p.Lys1269Ter stop_gained - - - 12070251 Coupry I , et al. (2002)
C>T p.Arg1498Ter stop_gained - - - 12070251 Coupry I , et al. (2002)
c.3096insT - frameshift_variant - - - 12070251 Coupry I , et al. (2002)
c.5170G>A p.Glu1724Lys missense_variant Unknown - - 38438125 et al. ()
C>A p.Ser23Ter stop_gained De novo - - 12070251 Coupry I , et al. (2002)
A>G p.Lys1520Arg missense_variant - - - 12070251 Coupry I , et al. (2002)
C>T p.Arg370Ter stop_gained De novo - - 12070251 Coupry I , et al. (2002)
c.4398T>A p.Tyr1466Ter stop_gained - - - 12070251 Coupry I , et al. (2002)
c.6127C>T p.Gln2043Ter stop_gained - - - 12070251 Coupry I , et al. (2002)
del7bp+ins2bp - splice_site_variant - - - 12070251 Coupry I , et al. (2002)
c.6244C>T p.Gln2082Ter stop_gained Unknown - Unknown 37799141 et al. ()
138delA+ins13bp - stop_gained De novo - - 12070251 Coupry I , et al. (2002)
c.406C>T p.Gln136Ter stop_gained Unknown - - 7630403 Petrij F , et al. (1995)
c.1069C>T p.Gln357Ter stop_gained De novo - - 7630403 Petrij F , et al. (1995)
c.2941G>A p.Ala981Thr missense_variant - - - 12070251 Coupry I , et al. (2002)
c.5933A>G p.Asn1978Ser missense_variant - - - 12070251 Coupry I , et al. (2002)
c.6661A>C p.Met2221Leu missense_variant - - - 12070251 Coupry I , et al. (2002)
c.6728C>T p.Ala2243Val missense_variant - - - 12070251 Coupry I , et al. (2002)
c.840dup p.Ser281Ter frameshift_variant - - - 12070251 Coupry I , et al. (2002)
c.2113+1G>A - splice_site_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.778C>T p.Gln260Ter stop_gained De novo - - 26788536 Wincent J , et al. (2016)
c.1827+1G>A - splice_site_variant De novo - - 26788536 Wincent J , et al. (2016)
c.3610-2A>G - splice_site_variant Unknown - - 29637745 Ajmone PF , et al. (2018)
c.1825_1827+9del - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.5635C>T p.Gln1879Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.3665+1G>A - splice_site_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.5131A>G p.Lys1711Glu missense_variant Familial Paternal - 38321498 et al. ()
c.3452G>A p.Trp1151Ter stop_gained De novo - - 26788536 Wincent J , et al. (2016)
c.3517C>T p.Arg1173Ter stop_gained Unknown - - 26788536 Wincent J , et al. (2016)
c.4078C>T p.Arg1360Ter stop_gained De novo - - 26788536 Wincent J , et al. (2016)
c.5635C>T p.Gln1879Ter stop_gained De novo - - 26788536 Wincent J , et al. (2016)
c.6211C>G p.Leu2071Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7082C>G p.Ser2361Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2044+1G>A - splice_site_variant Unknown - - 27848944 Trujillano D , et al. (2016)
c.4140G>C p.Val1380%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5354G>A p.Cys1785Tyr missense_variant De novo - - 30892814 Banka S , et al. (2019)
c.5357G>A p.Arg1786His missense_variant De novo - - 30892814 Banka S , et al. (2019)
c.5602C>T p.Pro1868Ser missense_variant De novo - - 30892814 Banka S , et al. (2019)
c.1780G>A p.Glu594Lys missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.5877del p.Val1960Ter stop_gained De novo - Simplex 34652060 Nishi E et al. (2021)
c.6188C>G p.Ser2063Ter stop_gained De novo - Simplex 34652060 Nishi E et al. (2021)
c.6241C>T p.Gln2081Ter stop_gained De novo - Simplex 34652060 Nishi E et al. (2021)
c.5128T>C p.Cys1710Arg missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5240T>G p.Leu1747Arg missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5357G>C p.Arg1786Pro missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5456G>T p.Cys1819Phe missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5488C>T p.Arg1830Trp missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5513G>A p.Cys1838Tyr missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5599C>T p.Pro1867Ser missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5602C>T p.Arg1868Trp missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5614A>G p.Met1872Val missense_variant De novo - - 27311832 Menke LA , et al. (2016)
c.5155C>G p.His1719Asp missense_variant De novo - - 29460469 Menke LA , et al. (2018)
c.5345C>T p.Ala1782Val missense_variant De novo - - 29460469 Menke LA , et al. (2018)
c.5485C>G p.Arg1829Gly missense_variant De novo - - 29460469 Menke LA , et al. (2018)
c.5600G>A p.Arg1867Gln missense_variant Unknown - - 29460469 Menke LA , et al. (2018)
c.5602C>T p.Arg1868Trp missense_variant De novo - - 29460469 Menke LA , et al. (2018)
c.5602C>T p.Pro1868Ser missense_variant De novo - - 29460469 Menke LA , et al. (2018)
c.5603G>A p.Arg1868Gln missense_variant De novo - - 29460469 Menke LA , et al. (2018)
c.5608G>A p.Ala1870Thr missense_variant De novo - - 29460469 Menke LA , et al. (2018)
c.5614A>G p.Met1872Val missense_variant De novo - - 29460469 Menke LA , et al. (2018)
c.4378C>T p.Arg1460Ter stop_gained De novo - Simplex 28940097 Anazi S , et al. (2017)
c.4613C>G p.Pro1538Arg missense_variant De novo - - 26788536 Wincent J , et al. (2016)
c.3514T>C p.Ser1172Pro missense_variant Unknown - - 29637745 Ajmone PF , et al. (2018)
c.2456C>T p.Pro819Leu missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.5237G>T p.Gly1746Val missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.3410A>G p.Tyr1137Cys missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.3868+5G>A - splice_site_variant De novo - Simplex 34795756 Elalaoui SC et al. (2021)
c.3800+3G>T - splice_region_variant De novo - Simplex 37463579 Kipkemoi P et al. (2023)
c.3374A>G p.Tyr1125Cys missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.5066T>C p.Leu1689Pro missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.2080G>A p.Val694Met missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.3160G>T p.Glu1054Ter stop_gained De novo - Simplex 34795756 Elalaoui SC et al. (2021)
c.4350C>A p.Tyr1450Ter stop_gained De novo - Simplex 34795756 Elalaoui SC et al. (2021)
c.6169C>T p.Gln2057Ter stop_gained De novo - Simplex 34795756 Elalaoui SC et al. (2021)
c.4597G>T p.Ala1533Ser missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.5614A>G p.Met1872Val missense_variant De novo - Simplex 34652060 Nishi E et al. (2021)
c.1238G>A p.Arg413Gln missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.5597_5599del p.Gln1866del inframe_deletion De novo - - 29460469 Menke LA , et al. (2018)
c.4393G>A p.Gly1465Arg missense_variant Unknown - - 31209962 Aspromonte MC , et al. (2019)
c.4616A>G p.Tyr1539Cys missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.2635C>T p.Pro879Ser missense_variant Familial Maternal - 24690944 Brett M , et al. (2014)
c.1069C>T p.Gln357Ter stop_gained Unknown Not maternal - 26788536 Wincent J , et al. (2016)
c.1585A>G p.Met529Val missense_variant De novo - Simplex 32277047 Chevarin M et al. (2020)
c.1931dup p.Pro645AlafsTer43 frameshift_variant De novo - - 12070251 Coupry I , et al. (2002)
c.4705A>G p.Thr1569Ala missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.5558A>C p.Gln1853Pro missense_variant De novo - Simplex 37463579 Kipkemoi P et al. (2023)
c.1109G>C p.Arg370Pro missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.3014dup p.Glu1006ArgfsTer7 frameshift_variant De novo - - 26788536 Wincent J , et al. (2016)
c.2617dup p.Gln873ProfsTer59 frameshift_variant Unknown - - 29637745 Ajmone PF , et al. (2018)
c.3609G>C p.Lys1203Asn missense_variant De novo - Simplex 34795756 Elalaoui SC et al. (2021)
c.5366A>G p.Asn1789Ser missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.2085del p.Gln695HisfsTer15 frameshift_variant De novo - Simplex 25768348 Yoo HJ , et al. (2015)
c.881dup p.Asn294LysfsTer56 frameshift_variant De novo - Simplex 28940097 Anazi S , et al. (2017)
c.4650G>C p.Lys1550Asn missense_variant De novo - Multiplex 31981491 Satterstrom FK et al. (2020)
c.2713del p.Gln905SerfsTer55 frameshift_variant Unknown - Unknown 12070251 Coupry I , et al. (2002)
c.4831del p.Ile1611SerfsTer95 frameshift_variant Unknown - Unknown 12070251 Coupry I , et al. (2002)
c.5570_5590del p.His1857_Gln1863del inframe_deletion De novo - Simplex 34652060 Nishi E et al. (2021)
c.4400_4401insATGT p.Met1468CysfsTer14 frameshift_variant De novo - - 26788536 Wincent J , et al. (2016)
c.2416_2417insGCTA p.Pro806ArgfsTer127 frameshift_variant - - Multiplex 31130284 Monies D , et al. (2019)
c.5478C>G p.Leu1826= missense_variant De novo - Possible multi-generational 27311832 Menke LA , et al. (2016)
c.5600G>A p.Arg1867Gln missense_variant De novo - Possible multi-generational 27311832 Menke LA , et al. (2016)
c.5371C>G p.His1791Asp missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.5485C>T p.His1829Tyr missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.3723-8C>T;c.3837-8C>T;c.3792-8C>T;c.3420-8C>T N/A intron_variant - - - 15830322 Barnby G , et al. (2005)
c.3137-2583T>C;c.3251-2583T>C;c.3206-2583T>C;c.2834-2583T>C N/A intron_variant - - - 15830322 Barnby G , et al. (2005)
c.4615-14G>A;c.4615-14G>C;c.4729-14G>A;c.4729-14G>C;c.4684-14G>A;c.4684-14G>C;c.4312-14G>A;c.4312-14 - intron_variant - - - 15830322 Barnby G , et al. (2005)
c.1217-32G>T;c.1331-32G>T - intron_variant - - - 15830322 Barnby G , et al. (2005)
c.1459+214T>C;c.1573+214T>C - intron_variant - - - 15830322 Barnby G , et al. (2005)
SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2020
1
icon
1

Score remained at 1

Description

Rare mutations in the CREBBP gene are associated with two distinct syndromes: Rubinstein-Taybi syndrome, which is frequently caused by either loss-of-function variants or submicroscopic 16p13.3 deletions; and Menke-Hennekam syndrome, which is caused by missense variants in exon 30 or 31 of the gene. A subset of individuals with either of these syndromes has been shown to display autism or autistic behaviors (Schorry et al., 2008; Wincent et al., 2015; Menke et al., 2016; Menke et al., 2018; Banka et al., 2019), although Galera et al., 2009 failed to validate the original findings of Schorry et al., 2008 for individuals with Rubinstein-Taybi syndrome. Genetic association between the CREBBP gene and ASD was observed in an IMGSAC cohort, but this association was not replicated in a second stage (Barnby et al., 2005). De novo missense variants in the CREBBP gene have also been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014; Krumm et al., 2015), as well as in a male ASD proband in Lim et al., 2017.

Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Rare mutations in the CREBBP gene are associated with two distinct syndromes: Rubinstein-Taybi syndrome, which is frequently caused by either loss-of-function variants or submicroscopic 16p13.3 deletions; and Menke-Hennekam syndrome, which is caused by missense variants in exon 30 or 31 of the gene. A subset of individuals with either of these syndromes has been shown to display autism or autistic behaviors (Schorry et al., 2008; Wincent et al., 2015; Menke et al., 2016; Menke et al., 2018; Banka et al., 2019), although Galera et al., 2009 failed to validate the original findings of Schorry et al., 2008 for individuals with Rubinstein-Taybi syndrome. Genetic association between the CREBBP gene and ASD was observed in an IMGSAC cohort, but this association was not replicated in a second stage (Barnby et al., 2005). De novo missense variants in the CREBBP gene have also been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014; Krumm et al., 2015), as well as in a male ASD proband in Lim et al., 2017.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

Rare mutations in the CREBBP gene are associated with two distinct syndromes: Rubinstein-Taybi syndrome, which is frequently caused by either loss-of-function variants or submicroscopic 16p13.3 deletions; and Menke-Hennekam syndrome, which is caused by missense variants in exon 30 or 31 of the gene. A subset of individuals with either of these syndromes has been shown to display autism or autistic behaviors (Schorry et al., 2008; Wincent et al., 2015; Menke et al., 2016; Menke et al., 2018; Banka et al., 2019), although Galera et al., 2009 failed to validate the original findings of Schorry et al., 2008 for individuals with Rubinstein-Taybi syndrome. Genetic association between the CREBBP gene and ASD was observed in an IMGSAC cohort, but this association was not replicated in a second stage (Barnby et al., 2005). De novo missense variants in the CREBBP gene have also been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014; Krumm et al., 2015), as well as in a male ASD proband in Lim et al., 2017.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
5
icon
4S

Decreased from 5 to 4S

Description

Rare mutations in the CREBBP gene are associated with two distinct syndromes: Rubinstein-Taybi syndrome, which is frequently caused by either loss-of-function variants or submicroscopic 16p13.3 deletions; and Menke-Hennekam syndrome, which is caused by missense variants in exon 30 or 31 of the gene. A subset of individuals with either of these syndromes has been shown to display autism or autistic behaviors (Schorry et al., 2008; Wincent et al., 2015; Menke et al., 2016; Menke et al., 2018; Banka et al., 2019), although Galera et al., 2009 failed to validate the original findings of Schorry et al., 2008 for individuals with Rubinstein-Taybi syndrome. Genetic association between the CREBBP gene and ASD was observed in an IMGSAC cohort, but this association was not replicated in a second stage (Barnby et al., 2005). De novo missense variants in the CREBBP gene have also been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014; Krumm et al., 2015), as well as in a male ASD proband in Lim et al., 2017.

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
4/1/2019
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Genotype-phenotype correlations in Rubinstein-Taybi syndrome.2008] [Socio-behavioral characteristics of children with Rubinstein-Taybi syndrome.2009] [Genotype-phenotype specificity in Menke-Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP.2019]
10/1/2017
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Expanding the genetic heterogeneity of intellectual disability.2017]
7/1/2017
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT.2005] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinste...2013] [Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.1995] [Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome.2002] [Whole exome sequencing for a patient with Rubinstein-Taybi syndrome reveals de novo variants besides an overt CREBBP mutation.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein-Taybi syndrome.2016] [CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
10/1/2016
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
7/1/2016
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT.2005] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinste...2013] [Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.1995] [Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome.2002] [Whole exome sequencing for a patient with Rubinstein-Taybi syndrome reveals de novo variants besides an overt CREBBP mutation.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein-Taybi syndrome.2016]
4/1/2015
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Whole exome sequencing for a patient with Rubinstein-Taybi syndrome reveals de novo variants besides an overt CREBBP mutation.2015] [Excess of rare, inherited truncating mutations in autism.2015]
1/1/2015
5
icon
5

Decreased from 5 to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
7/1/2014
No data
icon
5

Increased from No data to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

4/1/2014
No data
icon
5

Increased from No data to 5

Description

Genetic association has been found between the CREBBP gene and ASD in an IMGSAC cohort, but was not replicated in a second stage (Barnby et al., 2005). Rare mutations of the CREBBP gene have been identified in studies of patients with Rubinstein-Taybi syndrome (RTS), with some suggestion for increased autistic behavior (Schorry et al., 2008), that was not validated in a subsequent study (Galera et al., 2009).

Reports Added
[Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014]
Krishnan Probability Score

Score 0.59757463566427

Ranking 425/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999999999979

Ranking 31/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.926

Ranking 116/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.72057276341926

Ranking 1299/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 5

Ranking 278/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.56836094114003

Ranking 182/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
CNVs associated with CREBBP(1 CNVs)
Sort By:
16p13.3 68 Deletion-Duplication 98  /  537
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
BRCA2 breast cancer 2, early onset Human Protein Binding 675 P51587
C3ORF62 chromosome 3 open reading frame 62 Human Protein Binding 375341 Q6ZUJ4
CCND3 cyclin D3 Human Protein Binding 896 P30281
CTGF Connective tissue growth factor Human Protein Binding 1490 P29279
RPS6KA2 ribosomal protein S6 kinase polypeptide 2 Rat Protein Binding 117269 F1M7N7
STAT2 Signal transducer and activator of transcription 2 Human Protein Binding 6773 P52630
TXNDC11 thioredoxin domain containing 11 Human Protein Binding 51061 Q6PKC3
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