Human Gene Module / Chromosome 20 / ADNP

ADNPActivity-dependent neuroprotector homeobox

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
13 / 20
Rare Variants / Common Variants
41 / 0
Aliases
ADNP, ADNP1
Associated Syndromes
Helsmoortel-Van der Aa syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
20q13.13
Associated Disorders
DD/NDD, EPS, ID, 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

Potential transcription factor that may mediate some of the neuroprotective peptide VIP-associated effects involving normal growth and cancer proliferation. In brain, expression is stronger in the cerebellum and cortex regions.

Reports related to ADNP (20 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 Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. O'Roak BJ , et al. (2012) Yes -
3 Recent Recommendation A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Helsmoortel C , et al. (2014) No ASD, DD, ID, epilepsy (2 cases)
4 Recent recommendation The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism. Vandeweyer G , et al. (2014) Yes ID
5 Recent recommendation The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins. Oz S , et al. (2014) No -
6 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) Yes -
8 Recent recommendation Activity-dependent neuroprotective protein (ADNP) exhibits striking sexual dichotomy impacting on autistic and Alzheimer's pathologies. Malishkevich A , et al. (2015) No -
9 Support The Compassionate Side of Neuroscience: Tony Sermone's Undiagnosed Genetic Journey-ADNP Mutation. Gozes I , et al. (2015) Yes -
10 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
11 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. D'Gama AM , et al. (2015) Yes -
12 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Alvarez-Mora MI , et al. (2016) Yes -
13 Support Additional data on the clinical phenotype of Helsmoortel-Van der Aa syndrome associated with a novel truncating mutation in ADNP gene. Krajewska-Walasek M , et al. (2016) No ASD, DD, ID
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 Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
16 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
17 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No -
18 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
19 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
20 Support Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene. Takenouchi T , et al. (2017) No -
Rare Variants   (41)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1222_1223delAA p.Lys408ValfsTer31 frameshift_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.2156_2157insA p.Tyr719Ter frameshift_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.3280_3281insCC p.Gly1094ProfsTer5 frameshift_variant Familial Maternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.2496_2499delTAAA p.Asp832LysfsTer80 frameshift_variant De novo - - 24531329 Helsmoortel C , et al. (2014)
c.1211C>A p.Ser404Ter stop_gained De novo - - 24531329 Helsmoortel C , et al. (2014)
c.2153_2165delCTTACGAGCAAAT p.Thr718GlyfsTer12 frameshift_variant De novo - - 24531329 Helsmoortel C , et al. (2014)
c.2157C>G p.Tyr719Ter stop_gained De novo - - 24531329 Helsmoortel C , et al. (2014)
c.2491_2494delTTAA p.Lys831IlefsTer81 frameshift_variant De novo - - 24531329 Helsmoortel C , et al. (2014)
c.2808delC p.Tyr936Ter frameshift_variant De novo - - 24531329 Helsmoortel C , et al. (2014)
c.2491_2494delTTAA p.Lys831IlefsTer81 frameshift_variant De novo - - 24531329 Helsmoortel C , et al. (2014)
c.1930C>T p.Arg644Ter stop_gained Unknown - - 24531329 Helsmoortel C , et al. (2014)
c.118C>T p.Gln40Ter stop_gained De novo - Simplex 25169753 Vandeweyer G , et al. (2014)
c.642_649del p.Asn214fs frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2866_2869del p.Glu956fs frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2318_2319del p.Lys773fs frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1668G>C p.Gln556His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1553G>A p.Arg518His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2881G>T p.Asp961Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
 c.2495_2500​delATAAAG​insAG p.Asn832LysfsTer81 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1222_1224delAAGinsG p.Lys408ValfsTer31 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2157delCinsAC p.Tyr719Ter frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2495_2499​delATAAA​insA p.Asn832LysfsTer81 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1046_1047delTG p.Leu349ArgfsTer49 frameshift_variant De novo - Simplex 26168855 Gozes I , et al. (2015)
c.3281G>T p.Gly1094Val missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
- p.Thr443Ala missense_variant Unknown - - 26845707 Alvarez-Mora MI , et al. (2016)
c.2188C>T p.Arg730Ter stop_gained De novo - Simplex 27031564 Krajewska-Walasek M , et al. (2016)
c.2188C>T p.Arg730Ter stop_gained De novo - - 27479843 Lelieveld SH , et al. (2016)
delTGAC - frameshift_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.632T>A p.Leu211Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.3047dup p.Ala1017GlyfsTer6 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2288C>T p.Ser763Phe missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2157del p.Tyr719Ter frameshift_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.3170T>A p.Leu1057Ter stop_gained De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.3066_3072delCAGAGAGinsCAG p.Arg1023SerfsTer3 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.2491_2499delTTAAATAAAinsTTAAA p.Asn832LysfsTer81 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.2490_2494delATTAAinsA p.Leu831IlefsTer82 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.2213C>G p.Ser738Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.673C>T p.Arg225Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.1035_1038del p.Gln345fs frameshift_variant De novo - - 28263302 C Yuen RK , et al. (2017)
A>T - stop_gained De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.2157C>G p.Tyr719Ter stop_gained De novo - - 28407407 Takenouchi T , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Two de novo frameshift variants identified in unrelated simplex ASD cases (PMIDs 22495309 and 23160955). An additional seven de novo LoF variants were recently identified in patients with ASD, giving a current total of nine de novo LoF variants in ADNP gene in ASD cases; probability of detecting eight or more de novo truncating events in ADNP given as P=2.65 x 10-18 in this report. The frequency of shared clinical characteristics in ASD cases with LoF variants in ADNP (intellectual disability, facial dysmorphisms) led the authors to conclude that ADNP mutations resulted in an autism syndrome (PMID 24531329). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ADNP as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

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.

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."

04-01-2017
1S

Initial score established: 1S

Description

Two de novo frameshift variants identified in unrelated simplex ASD cases (PMIDs 22495309 and 23160955). An additional seven de novo LoF variants were recently identified in patients with ASD, giving a current total of nine de novo LoF variants in ADNP gene in ASD cases; probability of detecting eight or more de novo truncating events in ADNP given as P=2.65 x 10-18 in this report. The frequency of shared clinical characteristics in ASD cases with LoF variants in ADNP (intellectual disability, facial dysmorphisms) led the authors to conclude that ADNP mutations resulted in an autism syndrome (PMID 24531329). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ADNP as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Additional data on the clinical phenotype of Helsmoortel-Van der Aa syndrome associated with a novel truncating mutation in ADNP gene.2016] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene.2017] [A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP.2014] [Activity-dependent neuroprotective protein (ADNP) exhibits striking sexual dichotomy impacting on autistic and Alzheimer's pathologies.2015] [The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins.2014] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism.2014] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The Compassionate Side of Neuroscience: Tony Sermone's Undiagnosed Genetic Journey-ADNP Mutation.2015] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [Genome-wide characteristics of de novo mutations in autism.2016] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
CNVs associated with ADNP(1 CNVs)
20q13.13 7 Deletion-Duplication 13  /  31
Animal Models associated with ADNP(8 Models)
ADNP_1_KO_HM Genetic
ADNP_1_KO_HT Genetic
ADNP_1_KO_HT_NAP-1 RESCUE-Pharmaceutical
ADNP_1_KO_HT_NAP-2 RESCUE-Pharmaceutical
ADNP_1_KO_HT_NAP-3 RESCUE-Pharmaceutical
ADNP_1_KO_HT_SKIP-1 RESCUE-Pharmaceutical
ADNP_1_KO_HT_SKIP-2 RESCUE-Pharmaceutical
ADNP_2_KO_HT Genetic
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
2-Sep septin 2 Human Protein Binding 4735 Q15019
ADNP activity-dependent neuroprotector homeobox Human DNA Binding 23394 Q9H2P0
APOE apolipoprotein E Mouse Protein Binding 11816 P08226
ARID1A AT rich interactive domain 1A (SWI-like) Human Protein Binding 8289 O14497
CBX1 chromobox homolog 1 Human Protein Binding 10951 P83916
CBX3 chromobox homolog 3 Human Protein Binding 11335 Q13185
CBX5 chromobox homolog 5 Human Protein Binding 23468 P45973
CDC27 cell division cycle 27 Human Protein Binding 996 G3V1C4
CTSC cathepsin C Mouse Protein Binding 13032 P97821
CTSZ cathepsin Z Mouse Protein Binding 64138 Q9WUU7
EB1 Microtubule-associated protein RP/EB family member 1 Human Protein Binding 22919 Q15691
EB2 Microtubule-associated protein RP/EB family member 2 Human Protein Binding 10982 Q15555
EB3 Microtubule-associated protein RP/EB family member 3 Human Protein Binding 22924 Q9UPY8
EBNA1BP2 EBNA1 binding protein 2 Human Protein Binding 10969 H7C2Q8
EMD emerin Human Protein Binding 2010 P50402
H3F3A H3 histone, family 3A Human Protein Binding 3020 P84243
HBB hemoglobin, beta adult major chain Mouse DNA Binding 15129 P02088
HDAC1 histone deacetylase 1 Human Protein Binding 3065 Q13547
HDAC11 histone deacetylase 11 Human Protein Binding 79885 Q96DB2
HDAC7 histone deacetylase 7 Human Protein Binding 51564 Q8WUI4
MAP1LC3B microtubule-associated protein 1 light chain 3 beta Human Protein Binding 81631 Q9GZQ8
MAPRE1 microtubule-associated protein, RP/EB family, member 1 Human Protein Binding 22919 Q15691
Mapre2 microtubule-associated protein, RP/EB family, member 2 Mouse Protein Binding 212307 Q8R001
MAPRE3 microtubule-associated protein, RP/EB family, member 3 Human Protein Binding 22924 Q9UPY8
MTNR1A melatonin receptor 1A Mouse Protein Binding 17773 Q61184
MYC v-myc myelocytomatosis viral oncogene homolog (avian) Human Protein Binding 4609 P01106
MYL2 myosin, light polypeptide 2, regulatory, cardiac, slow Mouse Protein Binding 17906 P51667
NCAPH2 non-SMC condensin II complex, subunit H2 Human Protein Binding 29781 Q6IBW4
NEUROG1 neurogenin 1 Mouse Protein Binding 18014 P70660
NFIA nuclear factor I/A Human Protein Binding 4774 Q12857
PHGDH phosphoglycerate dehydrogenase Human Protein Binding 26227 O43175
POLG2 polymerase (DNA directed), gamma 2, accessory subunit Human Protein Binding NM_007215 E5KS15
QPRT Nicotinate-nucleotide pyrophosphorylase [carboxylating] Human Protein Binding 23475 Q15274
Rbfox1 RNA binding protein, fox-1 homolog (C. elegans) 1 Mouse RNA Binding 268859 Q9JJ43
RRS1 RRS1 ribosome biogenesis regulator homolog (S. cerevisiae) Human Protein Binding 23212 Q15050
SAP18 Sin3A-associated protein, 18kDa Human Protein Binding 10284 O00422
Sfpq splicing factor proline/glutamine-rich Mouse Protein Binding 71514 Q8VIJ6
SIRT7 sirtuin 7 Human Protein Binding 51547 Q9NRC8
Smarca2 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 Mouse Protein Binding 67155 Q6DIC0
SMARCA4 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 Human Protein Binding 6597 A7E2E1
SMARCC2 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily c, member 2 Human Protein Binding 6601 Q8TAQ2
Srcin1 SRC kinase signaling inhibitor 1 Mouse Protein Binding 56013 Q9QWI6
SUMO2 SMT3 suppressor of mif two 3 homolog 2 (S. cerevisiae) Human Protein Binding 6613 P61956
TOP3B topoisomerase (DNA) III beta Human Protein Binding 8940 O95985
Tubb2a tubulin, beta 2A class IIA Mouse Protein Binding 22151 Q7TMM9
ZNF524 Zinc finger protein 524 Human Protein Binding 147807 Q96C55
ZNF581 zinc finger protein 581 Human Protein Binding 51545 Q9P0T4
ZSCAN20 zinc finger and SCAN domain containing 20 Human Protein Binding 7579 P17040
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