Human Gene Module / Chromosome 18 / SMAD4

SMAD4SMAD family member 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 12
Rare Variants / Common Variants
12 / 0
Aliases
SMAD4, DPC4,  JIP,  MADH4,  MYHRS
Associated Syndromes
Myhre syndrome
Chromosome Band
18q21.2
Associated Disorders
-
Relevance to Autism

A recurrent damaging missense variant at p.Ile500 of the SMAD4 gene was originally identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a female proband with developmental delay (Deciphering Developmental Disorders Study, 2015). Geisheker et al., 2017 identified two novel ASD probands with a de novo damaging missense variant at p.Ile500, bringing the total number of de novo damaging missense variants at this position observed in NDD cases to 4 (P=2.07E-06, one-tailed binomial test, genome-wide correction); in contrast, no similar variants at p.Ile500 were observed in ExAC (allele count 0/45,376).

Molecular Function

This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to TGF-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The Smad proteins are subject to complex regulation by post-translational modifications.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SMAD4 (12 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 Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
3 Recent Recommendation Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
4 Recent Recommendation An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders Chen S , et al. (2018) No -
5 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism Cappi C , et al. (2019) No -
6 Support - Alonso-Gonzalez A et al. (2021) Yes -
7 Support - Pode-Shakked B et al. (2021) No -
8 Support - Zhou X et al. (2022) Yes -
9 Recent Recommendation - Xiangling Meng et al. (2023) No -
10 Support - Erica Rosina et al. (2024) No -
11 Support - Tamam Khalaf et al. (2024) No -
12 Support - Angela E Lin et al. () No ASD
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1333C>T p.Arg445Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1486C>T p.Arg496Cys missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.1449T>A p.Ser483Arg missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1486C>T p.Arg496Cys missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1498A>G p.Ile500Val missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.1499T>C p.Ile500Thr missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.904T>C p.Trp302Arg missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.1498A>G p.Ile500Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1499T>C p.Ile500Thr missense_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.1498A>G p.Ile500Val missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.1486C>T p.Arg496Cys missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.1498A>G p.Ile500Val missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A recurrent damaging missense variant at p.Ile500 of the SMAD4 gene was originally identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a female proband with developmental delay (Deciphering Developmental Disorders Study, 2015). Geisheker et al., 2017 identified two novel ASD probands with a de novo damaging missense variant at p.Ile500, bringing the total number of de novo damaging missense variants at this position observed in NDD cases to 4 (P=2.07E-06, one-tailed binomial test, genome-wide correction); in contrast, no similar variants at p.Ile500 were observed in ExAC (allele count 0/45,376).

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.

1/1/2021
2
icon
2

Score remained at 2

Description

A recurrent damaging missense variant at p.Ile500 of the SMAD4 gene was originally identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a female proband with developmental delay (Deciphering Developmental Disorders Study, 2015). Geisheker et al., 2017 identified two novel ASD probands with a de novo damaging missense variant at p.Ile500, bringing the total number of de novo damaging missense variants at this position observed in NDD cases to 4 (P=2.07E-06, one-tailed binomial test, genome-wide correction); in contrast, no similar variants at p.Ile500 were observed in ExAC (allele count 0/45,376).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
1/1/2020
2
icon
2

Score remained at 2

Description

A recurrent damaging missense variant at p.Ile500 of the SMAD4 gene was originally identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a female proband with developmental delay (Deciphering Developmental Disorders Study, 2015). Geisheker et al., 2017 identified two novel ASD probands with a de novo damaging missense variant at p.Ile500, bringing the total number of de novo damaging missense variants at this position observed in NDD cases to 4 (P=2.07E-06, one-tailed binomial test, genome-wide correction); in contrast, no similar variants at p.Ile500 were observed in ExAC (allele count 0/45,376).

Reports Added
[De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.2019]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A recurrent damaging missense variant at p.Ile500 of the SMAD4 gene was originally identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a female proband with developmental delay (Deciphering Developmental Disorders Study, 2015). Geisheker et al., 2017 identified two novel ASD probands with a de novo damaging missense variant at p.Ile500, bringing the total number of de novo damaging missense variants at this position observed in NDD cases to 4 (P=2.07E-06, one-tailed binomial test, genome-wide correction); in contrast, no similar variants at p.Ile500 were observed in ExAC (allele count 0/45,376).

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

Decreased from 3 to 3

Description

A recurrent damaging missense variant at p.Ile500 of the SMAD4 gene was originally identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a female proband with developmental delay (Deciphering Developmental Disorders Study, 2015). Geisheker et al., 2017 identified two novel ASD probands with a de novo damaging missense variant at p.Ile500, bringing the total number of de novo damaging missense variants at this position observed in NDD cases to 4 (P=2.07E-06, one-tailed binomial test, genome-wide correction); in contrast, no similar variants at p.Ile500 were observed in ExAC (allele count 0/45,376).

Reports Added
[An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.2018]
7/1/2017
icon
3

Increased from to 3

Description

A recurrent damaging missense variant at p.Ile500 of the SMAD4 gene was originally identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a female proband with developmental delay (Deciphering Developmental Disorders Study, 2015). Geisheker et al., 2017 identified two novel ASD probands with a de novo damaging missense variant at p.Ile500, bringing the total number of de novo damaging missense variants at this position observed in NDD cases to 4 (P=2.07E-06, one-tailed binomial test, genome-wide correction); in contrast, no similar variants at p.Ile500 were observed in ExAC (allele count 0/45,376).

Krishnan Probability Score

Score 0.49550307329095

Ranking 2927/25841 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 0.96743253593866

Ranking 2418/18225 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 0.81416924739966

Ranking 2479/18665 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 0.40108938246015

Ranking 1444/20870 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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