Human Gene Module / Chromosome 10 / ZMYND11

ZMYND11Zinc finger, MYND-type containing 11

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 11
Rare Variants / Common Variants
26 / 0
Aliases
ZMYND11, RP11-486H9.1,  BRAM1,  BS69
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
10p15.3
Associated Disorders
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 (11 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
Rare Variants   (26)
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.76C>T p.Arg26Trp missense_variant De novo NA - 28708303 Chrot E , et al. (2017)
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.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.1720T>C p.Cys574Arg missense_variant De novo NA Simplex 32097528 Yates TM , 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.

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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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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