Human Gene Module / Chromosome 20 / ZMYND8

ZMYND8zinc finger MYND-type containing 8

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
7 / 8
Rare Variants / Common Variants
20 / 0
EAGLE Score
4.5
Limited Learn More
Aliases
ZMYND8, PRKCBP1,  PRO2893,  RACK7
Associated Syndromes
-
Chromosome Band
20q13.12
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

De novo variants in the ZMYND8 gene, including two protein-truncating variants, have been identified in ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, and the Autism Genetic Resource Exchange (Iossifov et al., 2014; Yuen et al., 2017; Satterstrom et al., 2020). TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified ZMYND8 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Dias et al., 2022 reported 11 unrelated individuals with ZMYND8 variants presenting with a neurodevelopmental syndrome characterized by intellectual disability with variable cardiovascular, ophthalmologic and skeletal anomalies; four individuals were diagnosed with autism spectrum disorder, and two others presented with autistic features. Additional functional analysis of ZMYND8 missense variants identified in affected individuals in Dias et al., 2022 demonstrated disrupted protein interactions.

Molecular Function

The protein encoded by this gene is a receptor for activated C-kinase (RACK) protein. The encoded protein has been shown to bind in vitro to activated protein kinase C beta I. In addition, this protein is a cutaneous T-cell lymphoma-associated antigen. Finally, the protein contains a bromodomain and two zinc fingers, and is thought to be a transcriptional regulator.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ZMYND8 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Recent recommendation Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes -
5 Support - Mahjani B et al. (2021) Yes -
6 Support - Woodbury-Smith M et al. (2022) Yes -
7 Recent Recommendation - Dias KR et al. (2022) No ASD or autistic features, epilepsy/seizures
8 Support - Zhou X et al. (2022) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.882T>A p.Asp294Glu stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.237A>C p.Ser79%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.749G>A p.Gly250Glu missense_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.931T>C p.Trp311Arg missense_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.981C>G p.Phe327Leu missense_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.1060A>G p.Lys354Glu missense_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.2998G>A p.Glu1000Lys missense_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.3083A>G p.Lys1028Arg missense_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.3175T>A p.Cys1059Ser missense_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.3223T>C p.Trp1075Arg missense_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.3223T>C p.Trp1075Arg missense_variant Unknown - Simplex 35916866 Dias KR et al. (2022)
c.2032G>A p.Ala678Thr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1786A>G p.Ile596Val missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.3642del p.Ser1215ArgfsTer62 frameshift_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.3354G>A p.Ser1118%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1964dup p.Pro656AlafsTer5 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.969del p.Pro324LeufsTer4 frameshift_variant De novo - Simplex 35916866 Dias KR et al. (2022)
c.2154_2158del p.Arg719GlyfsTer5 frameshift_variant De novo - Simplex 32530565 Suzuki T et al. (2020)
c.1964dup p.Pro656AlafsTer10 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3621del p.Ser1208ArgfsTer62 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

S

Syndromic

See all Category S Genes

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."

4/1/2022
icon
1

Increased from to 1

Krishnan Probability Score

Score 0.49521466962211

Ranking 3118/25841 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.
Original Source
ExAC Score

Score 0.9999971063684

Ranking 364/18225 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
Original Source
Sanders TADA Score

Score 0.94522163219685

Ranking 16384/18665 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).
Original Source
Zhang D Score

Score 0.30929105006219

Ranking 2605/20870 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.
Original Source
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