Human Gene Module / Chromosome 5 / MSX2

MSX2msh homeobox 2

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
2 / 2
Rare Variants / Common Variants
5 / 0
Aliases
MSX2, CRS2,  FPP,  HOX8,  MSH,  PFM,  PFM1
Associated Syndromes
-
Chromosome Band
5q35.2
Associated Disorders
ID, EPS
Relevance to Autism

A de novo missense variant in the MSX2 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017). Four variants in the MSX2 gene, including a de novo frameshift variant, were identified in Japanese patients presenting with neurodevelopmental disorders in Suzuki et al., 2020; three of these patients were diagnosed with either autism spectrum disorder or PDD-NOS, while the fourth presented with autistic traits.

Molecular Function

This gene encodes a member of the muscle segment homeobox gene family. The encoded protein is a transcriptional repressor whose normal activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. The encoded protein may also have a role in promoting cell growth under certain conditions and may be an important target for the RAS signaling pathways.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MSX2 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
2 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes ID, epilepsy/seizures
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.*141dup - frameshift_variant De novo - Simplex 32530565 Suzuki T et al. (2020)
c.74G>T p.Gly25Val missense_variant Unknown - Unknown 32530565 Suzuki T et al. (2020)
c.175C>T p.Pro59Ser missense_variant Unknown - Unknown 32530565 Suzuki T et al. (2020)
c.635C>T p.Ala212Val missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.694G>A p.Ala232Thr missense_variant Familial Maternal Simplex 32530565 Suzuki T et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
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.

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
3

Increased from to 3

Krishnan Probability Score

Score 0.54575741894236

Ranking 1405/25841 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 0.42149241575751

Ranking 5866/18225 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 0.91501585793889

Ranking 8254/18665 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 -0.43230052601254

Ranking 18656/20870 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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