Human Gene Module / Chromosome 12 / SETD1B

SETD1BSET domain containing 1B

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
4 / 9
Rare Variants / Common Variants
7 / 0
Aliases
SETD1B, KMT2G,  Set1B
Associated Syndromes
12q24.31 microdeletion syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
12q24.31
Associated Disorders
ASD
Relevance to Autism

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Molecular Function

SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4; H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation.

Reports related to SETD1B (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A microdeletion at 12q24.31 can mimic beckwith-wiedemann syndrome neonatally. Baple E , et al. (2010) No -
2 Support Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability. Qiao Y , et al. (2012) No -
3 Primary The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
4 Support Microdeletion of 12q24.31: report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms. Palumbo O , et al. (2014) No -
5 Support An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic i... Labonne JD , et al. (2016) No -
6 Recent Recommendation De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism. Hiraide T , et al. (2018) Yes -
7 Support A novel de novo frameshift variant in SETD1B causes epilepsy. Den K , et al. (2019) No Autistic features
8 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Ruzzo EK , et al. (2019) Yes -
9 Support De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences. Hiraide T , et al. (2019) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.5524C>T p.Arg1842Trp missense_variant De novo NA - 29322246 Hiraide T , et al. (2018)
c.5575C>T p.Gln1859Ter missense_variant De novo NA - 29322246 Hiraide T , et al. (2018)
c.386T>G p.Val129Gly missense_variant De novo NA Simplex 31440728 Hiraide T , et al. (2019)
c.1658G>A p.Gly553Asp missense_variant De novo NA Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3884C>T p.Pro1295Leu missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.5645_5648del p.Tyr1882CysfsTer34 frameshift_variant De novo NA Simplex 31110234 Den K , et al. (2019)
c.5690_5695del p.Thr1897_Asp1899delinsAsn inframe_deletion De novo NA Simplex 25363768 Iossifov I , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Score Delta: Decreased from 4S to 3S

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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."

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

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

Decreased from 4S to 4S

Description

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

4/1/2018
icon
4.4 + S

Increased from to 4.4 + S

Description

4S

Krishnan Probability Score

Score 0.46887493608937

Ranking 8996/25841 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 0.02245631589155

Ranking 9299/18225 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 0.833

Ranking 210/239 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 0.94759847786217

Ranking 17341/18665 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).
Zhang D Score

Score 0.32667589781349

Ranking 2335/20870 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.
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