Human Gene Module / Chromosome 3 / MBD4

MBD4methyl-CpG binding domain protein 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
4 / 8
Aliases
MBD4, MED1
Associated Syndromes
-
Chromosome Band
3q21.3
Associated Disorders
-
Relevance to Autism

Genetic association and rare variants have been found in the MBD4 gene associated with autism in a Caucasian and African-American cohort (Cukier et al., 2010).

Molecular Function

The encoded protein forms a complex with MLH1, binds to methyl-CpG-containing DNA, has homology to bacterial DNA repair glycosylases/lyases, and displays endonuclease activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MBD4 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites Hendrich B , et al. (1999) No -
2 Highly Cited Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice Millar CB , et al. (2002) No -
3 Recent Recommendation DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45 Rai K , et al. (2008) No -
4 Recent Recommendation DNA demethylation in hormone-induced transcriptional derepression Kim MS , et al. (2009) No -
5 Primary Novel variants identified in methyl-CpG-binding domain genes in autistic individuals Cukier HN , et al. (2009) Yes -
6 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1400A>G p.Asn467Ser missense_variant - - - 19921286 Cukier HN , et al. (2009)
c.1295G>A p.Arg432His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
delAAGA p.Glu314fsTer316 frameshift_variant Familial Maternal Simplex 19921286 Cukier HN , et al. (2009)
c.1426del p.Leu476TrpfsTer9 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1183+68T>G;c.1201+50T>G;c.247+1415T>G T to G intron_variant - - - 19921286 Cukier HN , et al. (2009)
c.817G>A p.Ala273Thr missense_variant - - - 19921286 Cukier HN , et al. (2009)
c.335+27T>C;c.247+115T>C - intron_variant - - - 19921286 Cukier HN , et al. (2009)
c.336-46C>G;c.247+454C>G C to G intron_variant - - - 19921286 Cukier HN , et al. (2009)
c.1024T>C;c.247+1188T>C p.Ser342Pro missense_variant - - - 19921286 Cukier HN , et al. (2009)
c.1036G>A;c.247+1200G>A p.Glu346Lys missense_variant - - - 19921286 Cukier HN , et al. (2009)
c.1073T>C;c.247+1237T>C p.Ile358Thr missense_variant - - - 19921286 Cukier HN , et al. (2009)
c.1395C>T;c.1413C>T;c.459C>T p.(=) synonymous_variant - - - 19921286 Cukier HN , et al. (2009)
SFARI Gene score
2

Strong Candidate

There is minimal evidence for MBD4 in autism. In one study, Cukier et al. (2010) sequenced the gene in 226 autistic individuals. They identified two novel changes in the gene: one frameshift mutation that was maternally inherited, and one missense mutation in two cases that was not seen in 244 controls. MBD4 is also known to bind to the enhancer region of ERG2, a gene that is co-regulated with MECP2 (a category S gene).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

There is minimal evidence for MBD4 in autism. In one study, Cukier et al. (2010) sequenced the gene in 226 autistic individuals. They identified two novel changes in the gene: one frameshift mutation that was maternally inherited, and one missense mutation in two cases that was not seen in 244 controls. MBD4 is also known to bind to the enhancer region of ERG2, a gene that is co-regulated with MECP2 (a category S gene).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

There is minimal evidence for MBD4 in autism. In one study, Cukier et al. (2010) sequenced the gene in 226 autistic individuals. They identified two novel changes in the gene: one frameshift mutation that was maternally inherited, and one missense mutation in two cases that was not seen in 244 controls. MBD4 is also known to bind to the enhancer region of ERG2, a gene that is co-regulated with MECP2 (a category S gene).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

There is minimal evidence for MBD4 in autism. In one study, Cukier et al. (2010) sequenced the gene in 226 autistic individuals. They identified two novel changes in the gene: one frameshift mutation that was maternally inherited, and one missense mutation in two cases that was not seen in 244 controls. MBD4 is also known to bind to the enhancer region of ERG2, a gene that is co-regulated with MECP2 (a category S gene).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

There is minimal evidence for MBD4 in autism. In one study, Cukier et al. (2010) sequenced the gene in 226 autistic individuals. They identified two novel changes in the gene: one frameshift mutation that was maternally inherited, and one missense mutation in two cases that was not seen in 244 controls. MBD4 is also known to bind to the enhancer region of ERG2, a gene that is co-regulated with MECP2 (a category S gene).

Reports Added
[Novel variants identified in methyl-CpG-binding domain genes in autistic individuals.2009] [The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites.1999] [Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice.2002] [DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45.2008] [DNA demethylation in hormone-induced transcriptional derepression.2009] [The contribution of de novo coding mutations to autism spectrum disorder2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

There is minimal evidence for MBD4 in autism. In one study, Cukier et al. (2010) sequenced the gene in 226 autistic individuals. They identified two novel changes in the gene: one frameshift mutation that was maternally inherited, and one missense mutation in two cases that was not seen in 244 controls. MBD4 is also known to bind to the enhancer region of ERG2, a gene that is co-regulated with MECP2 (a category S gene).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

There is minimal evidence for MBD4 in autism. In one study, Cukier et al. (2010) sequenced the gene in 226 autistic individuals. They identified two novel changes in the gene: one frameshift mutation that was maternally inherited, and one missense mutation in two cases that was not seen in 244 controls. MBD4 is also known to bind to the enhancer region of ERG2, a gene that is co-regulated with MECP2 (a category S gene).

Krishnan Probability Score

Score 0.48511599242671

Ranking 7417/25841 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 1.6956103578176E-6

Ranking 14866/18225 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 0.7897150520599

Ranking 2041/18665 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
Larsen Cumulative Evidence Score

Score 4

Ranking 314/461 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.
Original Source
Zhang D Score

Score 0.32504058139524

Ranking 2357/20870 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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