Human Gene Module / Chromosome 10 / ZMYND11

ZMYND11Zinc finger, MYND-type containing 11

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 12
Rare Variants / Common Variants
38 / 0
Aliases
ZMYND11, RP11-486H9.1,  BRAM1,  BS69
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
10p15.3
Associated Disorders
ID, ASD
Relevance to Autism

A de novo LoF variant (splice-site) was identified in a simplex ASD case from the Simons Simplex Collection (Iossifov et al., 2012). More recently, five loss-of-function variants, one of which was de novo in origin and one which was inherited from a similarly affected parent, were identified in patients from DD/ID cohorts; one of these patients also presented with pervasive developmental disorder, and other patients presented with social difficulties and/or behavioral problems (Coe et al., 2014).

Molecular Function

Chromatin reader that specifically recognizes and binds histone H3.3 trimethylated at 'Lys-36' (H3.3K36me3) and regulates RNA polymerase II elongation. Colocalizes with highly expressed genes and functions as a transcription corepressor by modulating RNA polymerase II at the elongation stage. Acts as a tumor-suppressor by repressing a transcriptional program essential for tumor cell growth.

Reports related to ZMYND11 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
2 Recent Recommendation Refining analyses of copy number variation identifies specific genes associated with developmental delay. Coe BP , et al. (2014) No ASD
3 Support A de novo mutation in ZMYND11, a candidate gene for 10p15.3 deletion syndrome, is associated with syndromic intellectual disability. Cobben JM , et al. (2014) No -
4 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
6 Support Mutations in HECW2 are associated with intellectual disability and epilepsy. Halvardson J , et al. (2016) Yes -
7 Recent Recommendation Genome-wide association study of behavioral, physiological and gene expression traits in outbred CFW mice. Parker CC , et al. (2016) No -
8 Support A de novo missense mutation in ZMYND11 is associated with global developmental delay, seizures, and hypotonia. Moskowitz AM , et al. (2016) No -
9 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No Macrocephaly
10 Support Exome Pool-Seq in neurodevelopmental disorders. Popp B , et al. (2017) No Macrocephaly, hypotonia, aggression
11 Support ZMYND11-related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum. Yates TM , et al. (2020) No ASD or autistic features
12 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
Rare Variants   (38)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - stop_gained De novo NA Simplex 32097528 Yates TM , et al. (2020)
c.997-1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.466C>T p.Gln156Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1159-1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.8G>A p.Arg3His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.848T>C p.Leu283Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.850G>C p.Val284Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1799G>A p.Arg600Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.76C>T p.Arg26Trp missense_variant De novo NA - 28708303 Chrot E , et al. (2017)
c.8G>A p.Arg3His missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.976C>T p.Gln326Ter stop_gained Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.117-2A>T - splice_site_variant Unknown - Simplex 32097528 Yates TM , et al. (2020)
c.7C>T p.Arg3Cys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.803G>A p.Arg268His missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.630C>G p.Tyr210Ter stop_gained De novo NA Simplex 32097528 Yates TM , et al. (2020)
c.1089G>A p.Trp363Ter stop_gained De novo NA Simplex 32097528 Yates TM , et al. (2020)
c.1159-1G>A - splice_site_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.1053G>A p.Glu351= missense_variant De novo NA Simplex 32097528 Yates TM , et al. (2020)
c.744_745del p.Cys249SerfsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1720T>C p.Cys574Arg missense_variant De novo NA Simplex 32097528 Yates TM , et al. (2020)
c.581_582del p.Thr194MetfsTer3 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.1379dup p.Asn460LysfsTer2 frameshift_variant De novo NA - 32097528 Yates TM , et al. (2020)
c.1798C>T p.Arg600Trp missense_variant De novo NA Simplex 25281490 Cobben JM , et al. (2014)
c.1531C>T p.Gln511Ter stop_gained Familial Paternal Simplex 32097528 Yates TM , et al. (2020)
c.1084del p.Glu362LysfsTer3 frameshift_variant Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.1155_1158del p.Thr386ArgfsTer3 frameshift_variant Unknown - - 32097528 Yates TM , et al. (2020)
c.1332_1333del p.Lys446AlafsTer4 frameshift_variant Unknown - - 32097528 Yates TM , et al. (2020)
c.1756C>T p.Gln586Ter stop_gained Familial Maternal Multiplex 32097528 Yates TM , et al. (2020)
c.1636C>T p.Arg546Trp missense_variant De novo NA Simplex 27334371 Halvardson J , et al. (2016)
c.1262G>A p.Ser421Asn missense_variant De novo NA Simplex 27626064 Moskowitz AM , et al. (2016)
c.1597del p.Gln533ArgfsTer59 inframe_deletion De novo NA Unknown 25217958 Coe BP , et al. (2014)
c.292_293insC p.Asn98ThrfsTer26 frameshift_variant Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.1129del p.Ser377ProfsTer11 frameshift_variant De novo NA Simplex 32097528 Yates TM , et al. (2020)
c.456_459del p.Asn152LysfsTer22 frameshift_variant De novo NA Simplex 32097528 Yates TM , et al. (2020)
c.399del p.Met133IlefsTer19 frameshift_variant Familial Paternal Simplex 25217958 Coe BP , et al. (2014)
c.383del p.Ser128LeufsTer42 frameshift_variant Familial Paternal Simplex 29158550 Popp B , et al. (2017)
NM_006624.5:g.255918dup p.Thr70AsnfsTer12 frameshift_variant De novo NA Unknown 25217958 Coe BP , et al. (2014)
c.1798C>T p.Arg600Trp missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

Score Delta: Score remained at 3

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.

10/1/2020
3
icon
3

Score remained at 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

1/1/2020
3
icon
3

Score remained at 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

Reports Added
[New Scoring Scheme]
7/1/2018
4.5 + acc2
icon
3

Decreased from 4.5 + acc2 to 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

4/1/2018
3
icon
4.5 + acc2

Increased from 3 to 4.5 + acc2

Description

3

10/1/2017
3
icon
3

Increased from 3 to 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

7/1/2017
3
icon
3

Increased from 3 to 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

10/1/2016
3
icon
3

Increased from 3 to 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

7/1/2016
3
icon
3

Increased from 3 to 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

1/1/2016
3
icon
3

Increased from 3 to 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

10/1/2014
icon
3

Increased from to 3

Description

A de novo LoF variant in the ZMYND11 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

Krishnan Probability Score

Score 0.59500332703849

Ranking 448/25841 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 0.99996358635019

Ranking 559/18225 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
Iossifov Probability Score

Score 0.836

Ranking 206/239 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
Sanders TADA Score

Score 0.47375185068229

Ranking 395/18665 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 14

Ranking 142/461 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 0.62432484518091

Ranking 45/20870 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
LMP1 Latent membrane protein 1 HHV-4 Protein Binding 3783750 P03230
MAGEC2 Melanoma-associated antigen C2 Human Protein Binding 51438 Q9UBF1
UL122 Viral transcription factor IE2 HHV-5 Protein Binding 3077563 Q6SW29
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