Human Gene Module / Chromosome 3 / CTNNB1

CTNNB1Catenin (cadherin-associated protein), beta 1, 88kDa

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 16
Rare Variants / Common Variants
28 / 0
Aliases
CTNNB1, OK/SW-cl.35,  CTNNB
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
3p22.1
Associated Disorders
DD/NDD, ID, EPS, ASD
Relevance to Autism

De novo variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (Sanders et al. 2012a, 2012b)

Molecular Function

Key downstream component of the canonical Wnt signaling pathway. The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon.

Reports related to CTNNB1 (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
2 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
3 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. O'Roak BJ , et al. (2012) Yes -
4 Support Dominant -catenin mutations cause intellectual disability with recognizable syndromic features. Tucci V , et al. (2014) No Autistic features
5 Support A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency. Dubruc E , et al. (2014) No -
6 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
7 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
8 Recent recommendation De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Homsy J , et al. (2016) No ASD, DD, ID
9 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Alvarez-Mora MI , et al. (2016) Yes -
10 Support A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report. Winczewska-Wiktor A , et al. (2016) No -
11 Recent recommendation Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects. Dong F , et al. (2016) No -
12 Support Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Marchetto MC , et al. (2016) Yes -
13 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
14 Recent recommendation Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and -Catenin Functional Interactions to Enhance Synapse Formation. Xie Z , et al. (2016) No -
15 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No DD, ID, microcephaly
16 Support Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals. Kharbanda M , et al. (2016) No Hypotonia, spasticity, microcephaly
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type Author, Year
c.1652C>T p.Thr551Met missense_variant De novo - Simplex O'Roak BJ , et al. (2012)
c.1272_1275del p.Ser425ThrfsTer11 frameshift_variant De novo - - de Ligt J , et al. (2012)
c.925C>T p.Gln309Ter stop_gained Unknown Not maternal - de Ligt J , et al. (2012)
c.1543C>T p.Arg515Ter stop_gained De novo - - de Ligt J , et al. (2012)
c.1512G>A p.Trp504Ter stop_gained De novo - Simplex O'Roak BJ , et al. (2012)
c.705dup p.Gly236ArgfsTer35 frameshift_variant De novo - Simplex Tucci V , et al. (2014)
- - copy_number_loss De novo - Simplex Dubruc E , et al. (2014)
c.1981C>T p.Arg661Ter stop_gained De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.1038_1044​delGCTATCT​insGCT p.Val349AlafsTer9 frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.998dupA p.Tyr333Ter frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.1603C>T p.Arg535Ter stop_gained De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.1686_1690​delGGGGG​insGGGG p.Val564SerfsTer6 frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
T/G - splice_site_variant De novo - - Deciphering Developmental Disorders Study (2014)
delG - frameshift_variant De novo - - Homsy J , et al. (2016)
c.2255G>C p.Gly752Ala missense_variant Unknown - - Alvarez-Mora MI , et al. (2016)
c.232C>T p.Gln78Ter stop_gained De novo - Simplex Winczewska-Wiktor A , et al. (2016)
C>C/T Q/Ter stop_gained Unknown - - Marchetto MC , et al. (2016)
c.1420C>T p.Arg474Ter stop_gained De novo - - Lelieveld SH , et al. (2016)
c.607C>T p.Gln203Ter stop_gained De novo - - Lelieveld SH , et al. (2016)
c.1420C>T p.Arg474Ter stop_gained De novo - - Lelieveld SH , et al. (2016)
c.1925_1926del p.Glu642ValfsTer5 frameshift_variant De novo - Simplex Trujillano D , et al. (2016)
c.1981C>T p.Arg661Ter stop_gained De novo - Simplex Trujillano D , et al. (2016)
c.1801C>T p.Gln601Ter stop_gained De novo - - Kharbanda M , et al. (2016)
c.1603C>T p.Arg535Ter stop_gained De novo - - Kharbanda M , et al. (2016)
c.999C>G p.Tyr333Ter stop_gained De novo - - Kharbanda M , et al. (2016)
c.1420C>T p.Arg474Ter stop_gained De novo - - Kharbanda M , et al. (2016)
c.799_809delGAAGGAGCTAAinsGAA p.Gly268TrpfsTer5 frameshift_variant De novo - - Kharbanda M , et al. (2016)
c.1612C>T p.Gln538Ter stop_gained De novo - - Kharbanda M , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Two de novo variants (one nonsense, one missense) in the CTNNB1 gene were identified in unrelated simplex ASD cases (PMIDs 22495309 and 23160955). Three de novo LoF variants in CTNNB1 (two frameshift, one nonsense) have been identified in unrelated patients with a similar phenotypic profile: severe ID, absent or very limited speech, microcephaly, and spasticity (PMIDs 23033978 and 24614104). De novo LoF variants in CTNNB1 were identified in a total of six patients from the Deciphering Developmental Disorders study (PMID 25533962). A de novo LoF variant in CTNNB1 was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). Conditional knockout mice with CTNNB1-deficient parvalbumin interneurons exhibited significantly impaired object recognition and social interactions, elevated repetitive behaviors, and increased anxiety (Dong et al., 2016).

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of “accessory evidence” (indicated as “acc” in the score cards) could also boost a gene from category 4 to 3.

01-01-2017
3

Initial score established: 3

Description

Two de novo variants (one nonsense, one missense) in the CTNNB1 gene were identified in unrelated simplex ASD cases (PMIDs 22495309 and 23160955). Three de novo LoF variants in CTNNB1 (two frameshift, one nonsense) have been identified in unrelated patients with a similar phenotypic profile: severe ID, absent or very limited speech, microcephaly, and spasticity (PMIDs 23033978 and 24614104). De novo LoF variants in CTNNB1 were identified in a total of six patients from the Deciphering Developmental Disorders study (PMID 25533962). A de novo LoF variant in CTNNB1 was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). Conditional knockout mice with CTNNB1-deficient parvalbumin interneurons exhibited significantly impaired object recognition and social interactions, elevated repetitive behaviors, and increased anxiety (Dong et al., 2016).

Reports Added
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CNVs associated with CTNNB1(2 CNVs)
20q12-q13.11 1 Duplication 1  /  1
20q13.11 2 Deletion-Duplication 4  /  4
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AJAP1 Adherens junction-associated protein 1 Human Protein Binding 55966 Q9UKB5
AKT1 v-akt murine thymoma viral oncogene homolog 1 Human Protein Binding 207 P31749
AMOT angiomotin Human Protein Binding 154796 Q4VCS5
APC2 adenomatosis polyposis coli 2 Human RNA Binding 10297 O95996
BCL3 B-cell CLL/lymphoma 3 Human Protein Binding 602 P20749
Bcl9l B-cell CLL/lymphoma 9-like Mouse Protein Binding 80288 Q67FY2
BOC BOC cell adhesion associated, oncogene regulated Human Protein Binding 91653 Q96DN7
C6ORF26 Suppressor APC domain-containing protein 1 Human Protein Binding 401251 Q5SSQ6-2
CA9 Carbonic anhydrase 9 Human Protein Binding 768 Q16790
CALCOCO1 calcium binding and coiled-coil domain 2 Chicken Protein Binding 419993 E1BRX6
CBL Cas-Br-M (murine) ecotropic retroviral transforming sequence Human Protein Modification 867 P22681
CCNA1 Cyclin-A1 Human Protein Binding 8900 P78396
CCNE1 cyclin E1 Human Protein Binding 898 P24864
CDH11 Cadherin-11 Human Protein Binding 1009 P55287
cdh3-b Beta-catenin-interacting protein 1 Human Protein Binding 594865 Q9NSA3
CDH8 cadherin 8, type 2 Human Protein Binding 1006 P55286
CDON cell adhesion associated, oncogene regulated Human Protein Binding 50937 Q4KMG0
COPS3 COP9 constitutive photomorphogenic homolog subunit 3 (Arabidopsis) Human Protein Binding 8533 Q9UNS2
CSNK1D casein kinase 1, delta Rat Protein Modification 64462 Q06486
DDB1 damage-specific DNA binding protein 1, 127kDa Human Protein Binding 1642 Q16531
DDX1 DEAD (Asp-Glu-Ala-Asp) box helicase 1 Human Protein Binding 1653 A3RJH1
ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) Human Protein Binding 2064 P04626
FANCL Fanconi anemia, complementation group L Human Protein Modification 55120 Q9NW38
FOXO4 forkhead box O4 Human Protein Binding 4303 P98177
GLIS2 Zinc finger protein GLIS2 Human Protein Binding 84662 Q9BZE0
GRIK2 glutamate receptor, ionotropic, kainate 2 Rat Protein Binding 54257 P42260
HDAC6 histone deacetylase 6 Human Protein Modification 10013 Q9UBN7
HERC5 HECT and RLD domain containing E3 ubiquitin protein ligase 5 Human Protein Binding 51191 B4DXV3
HINT1 histidine triad nucleotide binding protein 1 Human Protein Binding 3094 P49773
HTT Huntingtin Human Protein Binding 3064 P42858
ISG15 ISG15 ubiquitin-like modifier Human Protein Binding 9636 P05161
ITGA3 integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) Human Protein Binding 3675 P26006
KAT2A K(lysine) acetyltransferase 2A Human Protein Binding 2648 Q92830
LATS2 LATS, large tumor suppressor, homolog 2 (Drosophila) Human Protein Binding 26524 Q9NRM7
LDHB lactate dehydrogenase B Human Protein Binding 3945 P07195
MAGI2 membrane associated guanylate kinase, WW and PDZ domain containing 2 Human Protein Binding 9863 Q86UL8
MAPK8 mitogen-activated protein kinase 8 Human Protein Modification 5599 P45983
MAPK9 mitogen-activated protein kinase 9 Human Protein Modification 5601 P45984
MEN1 multiple endocrine neoplasia I Human Protein Binding 4221 O00255
MICAL-L2 MICAL-like protein 2 Human Direct Regulation 79778 Q8IY33
NONO non-POU domain containing, octamer-binding Human Protein Binding 4841 Q15233
NUP62 nucleoporin 62kDa Human Protein Binding 23636 P37198
Pax6 paired box gene 6 Mouse Direct Regulation 18508 P63015
PCDH9 protocadherin 9 Human DNA Binding 5101 Q9HC56
PIN1 peptidylprolyl cis/trans isomerase, NIMA-interacting 1 Human Protein Binding 5300 Q13526
PITX2 paired-like homeodomain 2 Human Protein Binding 5308 Q99697
PML promyelocytic leukemia Human Protein Binding 5371 P29590
PROP1 Homeobox protein prophet of Pit-1 Human Protein Binding 5626 O75360
PRPF6 PRP6 pre-mRNA processing factor 6 homolog (S. cerevisiae) Human Protein Binding 24148 O94906
PTGS2 Prostaglandin G/H synthase 2 Human RNA Binding 5743 P35354
PTPN1 protein tyrosine phosphatase, non-receptor type 1 Human Protein Binding 5770 P18031
PTPRU protein tyrosine phosphatase, receptor type, U Human Protein Binding 10076 Q92729
RB1CC1 RB1-inducible coiled-coil 1 Human Protein Binding 9821 Q8TDY2
RBMX RNA binding motif protein, X-linked Human Protein Binding 27316 P38159
RPLP2 ribosomal protein, large, P2 Human Protein Binding 6181 P05387
RXRA retinoid X receptor, alpha Human Protein Binding 6256 F1D8Q5
SATB1 SATB homeobox 1 Human Protein Binding 6304 Q01826
SLAMF7 SLAM family member 7 Human Protein Binding 57823 Q9NQ25-3
SUV39H1 suppressor of variegation 3-9 homolog 1 (Drosophila) Human Protein Binding 6839 O43463
TAX1BP3 Tax1-binding protein 3 Mouse Protein Binding 30851 Q9DBG9
TIP60 Histone acetyltransferase KAT5 Human Protein Binding 10524 Q92993
UHRF2 ubiquitin-like with PHD and ring finger domains 2, E3 ubiquitin protein ligase Human Protein Binding 115426 Q96PU4
VCL vinculin Human Protein Binding 7414 B3KXA2
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