Human Gene Module / Chromosome 10 / ANK3

ANK3ankyrin 3

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
9 / 26
Rare Variants / Common Variants
23 / 8
Aliases
ANK3, RP11-369L1.1,  ANKYRIN-G
Associated Syndromes
Tourette syndrome
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
10q21.2
Associated Disorders
ASD, ID, EPS, ADHD, DD/NDD
Relevance to Autism

Three different missense mutations in the ANK3 gene, including a recurrent de novo mutation, were identified in four unrelated ASD patients in an exome sequencing report using cases from AGRE (Bi et al., 2012).

Molecular Function

Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems.

Reports related to ANK3 (25 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Baum AE , et al. (2007) No -
2 Positive Association Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Ferreira MA , et al. (2008) No -
3 Positive Association Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Schulze TG , et al. (2008) No -
4 Positive Association Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. Athanasiu L , et al. (2010) No -
5 Positive Association Molecular and genetic evidence for abnormalities in the nodes of Ranvier in schizophrenia. Roussos P , et al. (2011) No -
6 Positive Association Genome-wide association study identifies five new schizophrenia loci. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011) No -
7 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
8 Primary Mutations of ANK3 identified by exome sequencing are associated with autism susceptibility. Bi C , et al. (2012) Yes -
9 Recent Recommendation Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Iqbal Z , et al. (2013) Yes Epilepsy
10 Recent Recommendation Converging Evidence for Epistasis between ANK3 and Potassium Channel Gene KCNQ2 in Bipolar Disorder. Judy JT , et al. (2013) No -
11 Positive Association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
12 Recent Recommendation Ankyrin-G regulates neurogenesis and Wnt signaling by altering the subcellular localization of -catenin. Durak O , et al. (2014) No -
13 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
14 Recent Recommendation Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses. Smith KR , et al. (2014) No -
15 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
16 Support GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disabil... Bonnet-Brilhault F , et al. (2015) Yes -
17 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Karaca E , et al. (2015) No -
18 Support The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies. Schuch JB , et al. (2016) No -
19 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
20 Recent Recommendation Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder. Lopez AY , et al. (2016) No -
21 Support Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism. Chen R , et al. (2017) Yes -
22 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Willsey AJ , et al. (2017) No -
23 Support First de novo ANK3 nonsense mutation in a boy with intellectual disability, speech impairment and autistic features. Kloth K , et al. (2017) No Autistic features, macrocephaly
24 Recent Recommendation Disruption of the psychiatric risk gene Ankyrin 3 enhances microtubule dynamics through GSK3/CRMP2 signaling. Garza JC , et al. (2018) No -
25 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation Unknown - - 23390136 Iqbal Z , et al. (2013)
c.82C>T p.His28Tyr stop_gained Familial Paternal - 27824329 Wang T , et al. (2016)
c.1990G>T p.Gly664Ter stop_gained De novo NA Simplex 28687526 Kloth K , et al. (2017)
c.626C>T p.Thr209Met missense_variant De novo NA Simplex 28344757 Chen R , et al. (2017)
c.1217G>A p.Arg412Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1819G>C p.Val613Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2243C>T p.Ala748Val missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2243C>T p.Ala748Val missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.4705T>G p.Ser1569Ala missense_variant De novo NA Multiplex 22865819 Bi C , et al. (2012)
c.16+1G>A p.? splice_site_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.3644C>T p.Pro1215Leu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.6812T>C p.Met2271Thr missense_variant De novo NA Simplex 22495306 Sanders SJ , et al. (2012)
c.7267C>T p.Arg2423Cys missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.3662C>T p.Pro1221Leu missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.11159C>T p.Thr3720Met missense_variant Familial Inherited Simplex 22865819 Bi C , et al. (2012)
c.1448G>A p.Arg483Gln missense_variant Unknown Not maternal Simplex 30564305 Guo H , et al. (2018)
c.647A>G p.Lys216Arg missense_variant De novo NA Simplex 23934111 Epi4K Consortium , et al. (2013)
c.12763A>C p.Thr4255Pro missense_variant Familial Inherited Multiplex 22865819 Bi C , et al. (2012)
c.1808-1877del - frameshift_variant Familial Both parents Multiplex 23390136 Iqbal Z , et al. (2013)
c.9652C>T p.Leu3218Phe missense_variant Familial Both parents Multiplex 26539891 Karaca E , et al. (2015)
c.3727C>T p.Arg1243Cys missense_variant Familial Paternal Simplex 26055424 Bonnet-Brilhault F , et al. (2015)
c.11787A>T p.Ala3929%3D synonymous_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1570C>T:,c.1621C>T:,c.1603C>T p.Arg524Ter;p.Arg541Ter;p.Arg535Ter stop_gained De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.97-45940A>G;c.64-45940A>G;c.115-45940A>G - intron_variant - - - 20185149 Athanasiu L , et al. (2010)
c.96+74561T>C;c.63+31840T>C minor allele, G intron_variant - - - 18711365 Ferreira MA , et al. (2008)
c.97-140415G>A;c.64-140415G>A minor allele, T intron_variant - - - 18711365 Ferreira MA , et al. (2008)
c.96+152837A>G;c.63+110116A>G C/T intron_variant - - - 21926974 Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011)
c.1807+464G>A;c.4387+464G>A;c.4408+464G>A;c.4432+464G>A;c.4417+464G>A;c.4366+464G>A;c.4339+464G>A;c. - intron_variant - - - 17486107 Baum AE , et al. (2007)
c.1807+464G>A;c.4387+464G>A;c.4408+464G>A;c.4432+464G>A;c.4417+464G>A;c.4366+464G>A;c.4339+464G>A;c. - intron_variant - - - 21893642 Roussos P , et al. (2011)
c.1807+464G>A;c.4387+464G>A;c.4408+464G>A;c.4432+464G>A;c.4417+464G>A;c.4366+464G>A;c.4339+464G>A;c. - intron_variant - - - 19088739 Schulze TG , et al. (2008)
c.97-140415G>A;c.64-140415G>A C/T intron_variant - - - 19088739 Schulze TG , et al. (2008)
SFARI Gene score
1

High Confidence

Three different missense mutations in the ANK3 gene, including a recurrent de novo mutation, were identified in four unrelated ASD patients in an exome sequencing report using cases from AGRE in Bi et al., 2012. De novo missense variants in ANK3 have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2014) and the University of Illinois at Chicago ACE project (Chen et al., 2017), whereas inherited loss-of-function (LoF) and damaging missense variants in this gene have been observed in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). De novo LoF variants in ANK3 have been identified in probands presenting with Tourette syndrome (Willsey et al., 2017) and intellectual disability with autistic features and ADHD (Kloth et al., 2017), and homozygous variants in this gene have also been observed in individuals from multiplex consanguineous families presenting with intellectual disability (Iqbal et al., 2013; Karaca et al., 2015). ANK3 has also been shown to associate with bipolar disorder and schizophrenia in multiple studies (Baum et al., 2008; Ferreira et al., 2008; Schulze et al., 2009; Athanasiu et al., 2010; Roussos et al., 2011; Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium 2011).

Score Delta: Decreased from 3 to 1

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.

10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

Three different missense mutations in the ANK3 gene, including a recurrent de novo mutation, were identified in four unrelated ASD patients in an exome sequencing report using cases from AGRE in Bi et al., 2012. De novo missense variants in ANK3 have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2014) and the University of Illinois at Chicago ACE project (Chen et al., 2017), whereas inherited loss-of-function (LoF) and damaging missense variants in this gene have been observed in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). De novo LoF variants in ANK3 have been identified in probands presenting with Tourette syndrome (Willsey et al., 2017) and intellectual disability with autistic features and ADHD (Kloth et al., 2017), and homozygous variants in this gene have also been observed in individuals from multiplex consanguineous families presenting with intellectual disability (Iqbal et al., 2013; Karaca et al., 2015). ANK3 has also been shown to associate with bipolar disorder and schizophrenia in multiple studies (Baum et al., 2008; Ferreira et al., 2008; Schulze et al., 2009; Athanasiu et al., 2010; Roussos et al., 2011; Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium 2011).

Reports Added
[New Scoring Scheme]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

Three different missense mutations in the ANK3 gene, including a recurrent de novo mutation, were identified in four unrelated ASD patients in an exome sequencing report using cases from AGRE in Bi et al., 2012. De novo missense variants in ANK3 have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2014) and the University of Illinois at Chicago ACE project (Chen et al., 2017), whereas inherited loss-of-function (LoF) and damaging missense variants in this gene have been observed in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). De novo LoF variants in ANK3 have been identified in probands presenting with Tourette syndrome (Willsey et al., 2017) and intellectual disability with autistic features and ADHD (Kloth et al., 2017), and homozygous variants in this gene have also been observed in individuals from multiplex consanguineous families presenting with intellectual disability (Iqbal et al., 2013; Karaca et al., 2015). ANK3 has also been shown to associate with bipolar disorder and schizophrenia in multiple studies (Baum et al., 2008; Ferreira et al., 2008; Schulze et al., 2009; Athanasiu et al., 2010; Roussos et al., 2011; Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium 2011).

7/1/2018
4.4 + acc
icon
3

Decreased from 4.4 + acc to 3

Description

Three different missense mutations in the ANK3 gene, including a recurrent de novo mutation, were identified in four unrelated ASD patients in an exome sequencing report using cases from AGRE in Bi et al., 2012. De novo missense variants in ANK3 have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2014) and the University of Illinois at Chicago ACE project (Chen et al., 2017), whereas inherited loss-of-function (LoF) and damaging missense variants in this gene have been observed in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). De novo LoF variants in ANK3 have been identified in probands presenting with Tourette syndrome (Willsey et al., 2017) and intellectual disability with autistic features and ADHD (Kloth et al., 2017), and homozygous variants in this gene have also been observed in individuals from multiplex consanguineous families presenting with intellectual disability (Iqbal et al., 2013; Karaca et al., 2015). ANK3 has also been shown to associate with bipolar disorder and schizophrenia in multiple studies (Baum et al., 2008; Ferreira et al., 2008; Schulze et al., 2009; Athanasiu et al., 2010; Roussos et al., 2011; Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium 2011).

4/1/2018
3
icon
4.4 + acc

Increased from 3 to 4.4 + acc

Description

3

10/1/2017
icon
3

Increased from to 3

Description

Three different missense mutations in the ANK3 gene, including a recurrent de novo mutation, were identified in four unrelated ASD patients in an exome sequencing report using cases from AGRE in Bi et al., 2012. De novo missense variants in ANK3 have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2014) and the University of Illinois at Chicago ACE project (Chen et al., 2017), whereas inherited loss-of-function (LoF) and damaging missense variants in this gene have been observed in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). De novo LoF variants in ANK3 have been identified in probands presenting with Tourette syndrome (Willsey et al., 2017) and intellectual disability with autistic features and ADHD (Kloth et al., 2017), and homozygous variants in this gene have also been observed in individuals from multiplex consanguineous families presenting with intellectual disability (Iqbal et al., 2013; Karaca et al., 2015). ANK3 has also been shown to associate with bipolar disorder and schizophrenia in multiple studies (Baum et al., 2008; Ferreira et al., 2008; Schulze et al., 2009; Athanasiu et al., 2010; Roussos et al., 2011; Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium 2011).

Krishnan Probability Score

Score 0.58725676970654

Ranking 502/25841 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.
ExAC Score

Score 0.99999999999992

Ranking 27/18225 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
Sanders TADA Score

Score 0.95067727453587

Ranking 18586/18665 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).
Larsen Cumulative Evidence Score

Score 8

Ranking 217/461 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.
Zhang D Score

Score 0.45223721018154

Ranking 900/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
APC adenomatous polyposis coli Human RNA Binding 324 P25054
ARHGAP22 Rho GTPase activating protein 22 Human Protein Binding 58504 Q7Z5H3
C10ORF47 proline and serine-rich protein 2 Human Protein Binding 254427 Q86WR7
C16ORF70 chromosome 16 open reading frame 70 Human Protein Binding 80262 Q9BSU1
CDH1 cadherin 1, type 1, E-cadherin (epithelial) Human Protein Binding 999 P12830
CDH5 Cadherin-5 Human Protein Binding 1003 P33151
CNGB1 cyclic nucleotide gated channel beta 1 Human Protein Binding 1258 Q14028
DAG1 dystroglycan 1 (dystrophin-associated glycoprotein 1) Human Protein Binding 1605 Q14118
DOK4 Docking protein 4 Human Protein Binding 55715 Q8TEW6
Fadd Fas (TNFRSF6)-associated via death domain Mouse Protein Binding 14082 Q61160
Fas Fas(TNF receptor superfamily member 6) Mouse Protein Binding 14102 P25446
FEZ1 fasciculation and elongation protein zeta 1 (zygin I) Human Protein Binding 9638 Q99689
FLNC filamin C, gamma Human Protein Binding 2318 Q14315
Gja1 gap junction protein, alpha 1 Rat Protein Binding 24392 P08050
HOOK1 hook homolog 1 (Drosophila) Human Protein Binding 51361 Q9UJC3
Kcnc1 potassium voltage gated channel, Shaw-related subfamily, member 1 Rat Protein Binding 25327 P25122
KCNQ2 potassium voltage-gated channel, KQT-like subfamily, member 2 Human Protein Binding 3785 O43526
KCNQ3 potassium voltage-gated channel, KQT-like subfamily, member 3 Human Protein Binding 3786 O43525
LILRB3 Leukocyte immunoglobulin-like receptor subfamily B member 3 Human Protein Binding 102725035 O75022-2
MAGED1 melanoma antigen family D, 1 Human Protein Binding 9500 Q9Y5V3
MAPK6 mitogen-activated protein kinase 6 Human Protein Binding 5597 Q16659
MIR34A microRNA 34a Human RNA Binding 407040 N/A
Nde1 nudE neurodevelopment protein 1 Rat Protein Binding 83836 Q9ES39
NEXN Nexilin Human Protein Binding 91624 Q0ZGT2
Pik3r1 phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 1 (p85 alpha) Mouse Protein Binding 18708 P26450
Pkp2 plakophilin 2 Rat Protein Binding 287925 N/A
PLEC plectin Human Protein Binding 5339 Q15149
PWP1 PWP1 homolog (S. cerevisiae) Human Protein Binding 11137 Q13610
RHBG Rh family, B glycoprotein (gene/pseudogene) Human Protein Binding 57127 Q9H310
Scn1b sodium channel, voltage-gated, type I, beta Rat Protein Binding 29686 Q00954
SCN2A sodium channel, voltage-gated, type II, alpha subunit Human Protein Binding 6326 Q99250
Scn5a sodium channel, voltage-gated, type V, alpha subunit Rat Protein Binding 25665 P15389
SCN8A sodium channel, voltage gated, type VIII, alpha subunit Human Protein Binding 6334 Q9UQD0
Scnn1b sodium channel, nonvoltage-gated 1, beta Rat Protein Binding 24767 P37090
SMAD2 SMAD family member 2 Human Protein Binding 4087 Q15796
SMAD3 SMAD family member 3 Human Protein Binding 4088 P84022
Sptbn4 spectrin beta, non-erythrocytic 4 Mouse Protein Binding 80297 E9PZC2
Tiam1 T-cell lymphoma invasion and metastasis 1 Mouse Protein Binding 21844 Q60610
UXS1 UDP-glucuronate decarboxylase 1 Human Protein Binding 80146 Q8NBZ7
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We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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