Human Gene Module / Chromosome 16 / ANKRD11

ANKRD11ankyrin repeat domain 11

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
9 / 27
Rare Variants / Common Variants
47 / 0
Aliases
ANKRD11, T13,  LZ16,  ANCO-1
Associated Syndromes
KBG syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
16q24.3
Associated Disorders
ADHD, EPS, ID, ASD
Relevance to Autism

Studies have identified rare mutations in the ANKRD11 gene with autism.

Molecular Function

Transcription factor that may recruit HDACs to the p160 coactivators/nuclear receptor complex to inhibit ligand-dependent transactivation. Defects in ANKRD11 are the cause of KBG syndrome (KBGS) [MIM:148050], a syndrome characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement that includes global developmental delay, seizures, and intellectual disability.

Reports related to ANKRD11 (27 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Identification of a novel family of ankyrin repeats containing cofactors for p160 nuclear receptor coactivators. Zhang A , et al. (2004) No -
2 Recent Recommendation Subcellular localization of ankyrin repeats cofactor-1 regulates its corepressor activity. Zhang A , et al. (2007) No -
3 Primary Structural variation of chromosomes in autism spectrum disorder. Marshall CR , et al. (2008) Yes -
4 Recent Recommendation Ankyrin repeats-containing cofactors interact with ADA3 and modulate its co-activator function. Li CW , et al. (2008) No -
5 Recent Recommendation Identification of ANKRD11 as a p53 coactivator. Neilsen PM , et al. (2008) No -
6 Support Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome. Willemsen MH , et al. (2009) Yes -
7 Support Haploinsufficiency of ANKRD11 causes mild cognitive impairment, short stature and minor dysmorphisms. Isrie M , et al. (2011) No ADHD
8 Support Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Sirmaci A , et al. (2011) No ID
9 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ... Brett M , et al. (2014) Yes MCA
10 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
11 Support De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Dong S , et al. (2014) No -
12 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
13 Recent recommendation Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations. Ockeloen CW , et al. (2014) No ASD, ID, ADHD, epilepsy
14 Support Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Soden SE , et al. (2014) No -
15 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) Yes -
16 Recent Recommendation Ankrd11 is a chromatin regulator involved in autism that is essential for neural development. Gallagher D , et al. (2015) No -
17 Support Whole exome sequencing in females with autism implicates novel and candidate genes. Butler MG , et al. (2015) Yes -
18 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
19 Support Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate. Charng WL , et al. (2016) No -
20 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
21 Support Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of ANKRD11. Goldenberg A , et al. (2016) No -
22 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. Martnez F , et al. (2016) No ID, autistic behavior, stereotypic behavior
23 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
24 Support Clinical and genetic aspects of KBG syndrome. Low K , et al. (2016) No -
25 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
26 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No -
27 Support KBG syndrome involving a single-nucleotide duplication in ANKRD11. Kleyner R , et al. (2016) No ASD, ID, epilepsy/seizures
Rare Variants   (47)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type Author, Year
- - copy_number_loss De novo - Simplex Marshall CR , et al. (2008)
- - copy_number_loss De novo - - Willemsen MH , et al. (2009)
- - copy_number_loss De novo - - Willemsen MH , et al. (2009)
- - copy_number_loss De novo - - Willemsen MH , et al. (2009)
- - copy_number_loss De novo - - Willemsen MH , et al. (2009)
- - copy_number_loss De novo - Simplex Isrie M , et al. (2011)
- - copy_number_loss De novo - Simplex Isrie M , et al. (2011)
c.7570-1G>C p.Glu2524_Lys2525del splice_site_variant Familial Paternal Multi-generational Sirmaci A , et al. (2011)
c.2305delT p.Ser769GlnfsTer8 frameshift_variant De novo - Simplex Sirmaci A , et al. (2011)
c.7189C>T p.Gln2397Ter stop_gained De novo - Simplex Sirmaci A , et al. (2011)
c.5953_5954delCA p.Gln1985GlufsTer46 frameshift_variant De novo - Simplex Sirmaci A , et al. (2011)
c.6071_6084delCGTACGCTCTGCCC p.Pro2024ArgfsTer3 frameshift_variant De novo - Simplex Sirmaci A , et al. (2011)
c.6868C>T p.Pro2290Ser missense_variant Familial Maternal - Brett M , et al. (2014)
c.4083C>A p.His1363Gln missense_variant Familial Maternal Multiplex Redin C , et al. (2014)
c.2175_2178del p.Asn725fs frameshift_variant De novo - Simplex Dong S , et al. (2014)
c.1903_1907del p.Lys635fs frameshift_variant De novo - Simplex Iossifov I , et al. (2014)
c.7481dup p.Pro2495fs frameshift_variant Familial Maternal Multi-generational Ockeloen CW , et al. (2014)
c.4391_4392del p.Lys1464fs frameshift_variant De novo - - Ockeloen CW , et al. (2014)
c.6184del p.Leu2062fs frameshift_variant De novo - - Ockeloen CW , et al. (2014)
c.3123_3126del p.Ile1042fs frameshift_variant De novo - - Ockeloen CW , et al. (2014)
c.1460_1463del p.Glu487fs frameshift_variant Unknown - - Ockeloen CW , et al. (2014)
c.1903_1907del p.Lys635fs frameshift_variant De novo - - Ockeloen CW , et al. (2014)
c.3832A>T p.Lys1278Ter stop_gained Familial - Multi-generational Ockeloen CW , et al. (2014)
c.2751dup p.Glu918Ter stop_gained De novo - - Ockeloen CW , et al. (2014)
c.3382_3383del p.Asp1128fs frameshift_variant De novo - - Ockeloen CW , et al. (2014)
c.1903_1907del p.Lys635fs frameshift_variant De novo - - Ockeloen CW , et al. (2014)
c.6513dup p.Gly2172fs frameshift_variant De novo - - Ockeloen CW , et al. (2014)
c.1318C>T p.Arg440Ter stop_gained Familial - Multi-generational Ockeloen CW , et al. (2014)
c.1385_1388delCAAA p.Thr462LysfsTer47 frameshift_variant De novo - - Soden SE , et al. (2014)
c.3703_3706del p.Lys1235ArgfsTer82 frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.2407_2412delAAAAAAinsA p.Lys803ArgfsTer5 frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
p.4103_4104del p.Lys1368ArgfsTer17 frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.2408_2412del p.Lys803ArgfsTer5 frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.1897_1907delAAAACAAAACinsAAAACA p.Lys635GlnfsTer26 frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.1801C>T p.Arg601Ter stop_gained De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.3582delG p.Gly1194fs frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.3436_3461del p.Thr1146LysfsTer164 frameshift_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.1382C>G p.Thr461Arg missense_variant Unknown - Multiplex Butler MG , et al. (2015)
c.5317G>T p.Glu1773Ter stop_gained De novo - Simplex Charng WL , et al. (2016)
c.4965del p.Glu1656fs frameshift_variant De novo - - Lelieveld SH , et al. (2016)
c.2092_2096del p.Glu698fs frameshift_variant De novo - - Lelieveld SH , et al. (2016)
c.2398_2401del p.Leu802fs frameshift_variant De novo - - Lelieveld SH , et al. (2016)
c.3369_3372delTGAG p.Ser1123ArgfsTer194 frameshift_variant Familial Paternal Multi-generational Martnez F , et al. (2016)
delT - intron_variant - - Unknown Doan RN , et al. (2016)
c.389A>G p.Asn130Ser missense_variant Familial Paternal - Wang T , et al. (2016)
c.7570-2A>G p.? splice_site_variant De novo - - Trujillano D , et al. (2016)
c.6015dupA p.Gly2006ArgfsTer26 frameshift_variant De novo - Simplex Kleyner R , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

ANKRD11 is in an ASD-associated multi-genic CNV on chromosome 16q24.3 (Willemsen et al., 2010; Marshall et al., 2008). Two de novo LoF variants in the ANKRD11 gene (both frameshift) have been identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). Mutations in ANKRD11 are also responsible for KBG syndrome (OMIM 148050), which is characterized by developmental delay/intellectual disability and, in some cases, autism (PMID 21782149, 19597979). A comprehensive clinical and genetic evaluation of 20 patients with KBG syndrome from 13 families published in 2014 found that many patients displayed behavioral abnormalities such as ASD (PMID 25424714). In this report, de novo LoF variants in ANKRD11 were observed in three KBG patients that also presented with ASD (two frameshift, one nonsense), while another frameshift variant in ANKRD11 segregated with disease in a multi-generational pedigree in which a mother with intellectual disability and autistic features transmitted this variant to four affected children, all of whom presented with ASD and intellectual disability. Clinical evaluation of 32 patients with KBG syndrome in Low et al., 2016 found that 8 out of 32 cases (25%) had a formal diagnosis of ASD, with an additional case presenting with some autistic features.

2

Strong Candidate

See all Category 2 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."

01-01-2017
2S

Initial score established: 2S

Description

ANKRD11 is in an ASD-associated multi-genic CNV on chromosome 16q24.3 (Willemsen et al., 2010; Marshall et al., 2008). Two de novo LoF variants in the ANKRD11 gene (both frameshift) have been identified in ASD probands from the Simons Simplex Collection (PMIDs 25284784, 25363768). Mutations in ANKRD11 are also responsible for KBG syndrome (OMIM 148050), which is characterized by developmental delay/intellectual disability and, in some cases, autism (PMID 21782149, 19597979). A comprehensive clinical and genetic evaluation of 20 patients with KBG syndrome from 13 families published in 2014 found that many patients displayed behavioral abnormalities such as ASD (PMID 25424714). In this report, de novo LoF variants in ANKRD11 were observed in three KBG patients that also presented with ASD (two frameshift, one nonsense), while another frameshift variant in ANKRD11 segregated with disease in a multi-generational pedigree in which a mother with intellectual disability and autistic features transmitted this variant to four affected children, all of whom presented with ASD and intellectual disability. Clinical evaluation of 32 patients with KBG syndrome in Low et al., 2016 found that 8 out of 32 cases (25%) had a formal diagnosis of ASD, with an additional case presenting with some autistic features.

Reports Added
[]
CNVs associated with ANKRD11(3 CNVs)
5q14.3 14 Deletion-Duplication 27  /  90
8q21 1 Deletion 1  /  1
8q21.3 13 Deletion-Duplication 22  /  81
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
BZRAP1 benzodiazapine receptor (peripheral) associated protein 1 Human Protein Binding 9256 O95153
CDCA7L cell division cycle associated 7-like Human Protein Binding 55536 Q96GN5
Fzd3 frizzled homolog 3 (Drosophila) Mouse Direct Regulation 14365 Q61086
GPS2 G protein pathway suppressor 2 Human Protein Binding 2874 Q13227
HDAC3 Histone deacetylase 3 Human Protein Binding 8841 O15379
HDAC4 histone deacetylase 4 Human Protein Binding 9759 P56524
HDAC5 Histone deacetylase 5 Human Protein Binding 10014 Q9UQL6
HOOK2 hook homolog 2 (Drosophila) Human Protein Binding 29911 Q96ED9
IKZF1 IKAROS family zinc finger 1 (Ikaros) Human Protein Binding 10320 Q13422
KIAA1712 centrosomal protein 44kDa Human Protein Binding NM_001040157 Q9C0F1
Kmt2e lysine (K)-specific methyltransferase 2E Mouse Direct Regulation 69188 Q3UG20
MKRN3 makorin ring finger protein 3 Human Protein Binding 7681 Q13064
NCOA2 nuclear receptor coactivator 2 Human Protein Binding 10499 Q15596
NCOA3 nuclear receptor coactivator 3 Human Protein Binding 8202 Q9Y6Q9
Ncor1 nuclear receptor co-repressor 1 Mouse Direct Regulation 20185 Q60974
Notch1 notch 1 Mouse Direct Regulation 18128 Q01705
PDE4DIP phosphodiesterase 4D interacting protein Human Protein Binding 9659 Q5VU43
Slc1a2 solute carrier family 1 (glial high affinity glutamate transporter), member 2 Mouse Direct Regulation 20511 P43006
Sox6 SRY-box containing gene 6 Mouse Direct Regulation 20679 P40645
TADA3 transcriptional adaptor 3 Human Protein Binding 10474 O75528
TFIP11 tuftelin interacting protein 11 Human Protein Binding 24144 Q9UBB9
TRIM37 tripartite motif containing 37 Human Protein Binding NM_015294 A8K0V9
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