Human Gene Module / Chromosome X / MSL3

MSL3MSL complex subunit 3

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
2 / 7
Rare Variants / Common Variants
38 / 0
EAGLE Score
13.9
Strong Learn More
Aliases
MSL3, MRSXBA,  MRXS36,  MRXSBAL1, MSL3
Associated Syndromes
Basilicata-Akhtar syndrome
Chromosome Band
Xp22.2
Associated Disorders
ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Brunet et al., 2020 delineated the genotypic and phenotypic spectrum of 25 individuals (15 males, 10 females) with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome) and found that 10/20 (50%) individuals had a diagnosis of autism spectrum disorder. De novo likely gene-disruptive (dnLGD) variants in the MSL3 gene were identified in an ASD proband from the SPARK cohort (Wang et al., 2020) and in four probands from the Deciphering Developmental Disorders study in 2017, while a de novo missense variant in MSL3 was identified in a female ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020. Single-molecular molecular inversion probe (smMIP) sequencing of 125 genes in over 16,000 cases with neurodevelopmental disorders in Wang et al., 2020 identified an additional likely gene-disruptive variant in an ASD proband from the AGRE cohort.

Molecular Function

This gene encodes a nuclear protein that is similar to the product of the Drosophila male-specific lethal-3 gene. The Drosophila protein plays a critical role in a dosage-compensation pathway, which equalizes X-linked gene expression in males and females. Thus, the human protein is thought to play a similar function in chromatin remodeling and transcriptional regulation, and it has been found as part of a complex that is responsible for histone H4 lysine-16 acetylation. Hemizygous or heterozygous mutations in the MSL3 gene are responsible for Basilicata-Akhtar syndrome (MRXSBA; OMIM 301032), a disorder characterized by global developmental delay apparent from infancy, feeding difficulties, hypotonia, and poor or absent speech (Basilicata et al., 2018).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MSL3 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
2 Support De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation Basilicata MF et al. (2018) No -
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
5 Primary Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder Brunet T et al. (2020) No ASD
6 Support - Brunet T et al. (2021) No ID
7 Support - Axel Schmidt et al. (2024) No ASD, epilepsy/seizures
Rare Variants   (38)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 33173220 Brunet T et al. (2020)
c.589-1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1193C>A p.Ser398Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.1237C>T p.Gln413Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1453G>T p.Asp485Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.982del p.Ala328LeufsTer9 frameshift_variant De novo - - 28135719 et al. (2017)
c.1342_1345del p.Phe448Ter frameshift_variant De novo - - 28135719 et al. (2017)
c.902dup p.Leu302PhefsTer18 frameshift_variant De novo - - 28135719 et al. (2017)
c.913C>T p.Gln305Ter stop_gained De novo - Simplex 33173220 Brunet T et al. (2020)
c.961C>T p.Gln321Ter stop_gained De novo - Simplex 33173220 Brunet T et al. (2020)
c.1430+1G>A - splice_site_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.1430+1G>A - splice_site_variant De novo - Simplex 33619735 Brunet T et al. (2021)
c.1105C>T p.Gln369Ter stop_gained De novo - Simplex 33173220 Brunet T et al. (2020)
c.1314C>A p.Tyr438Ter stop_gained De novo - Simplex 33173220 Brunet T et al. (2020)
c.1372C>T p.Arg458Ter stop_gained De novo - Simplex 33173220 Brunet T et al. (2020)
c.1314C>A p.Tyr438Ter stop_gained De novo - Simplex 33619735 Brunet T et al. (2021)
c.865A>T p.Lys289Ter stop_gained De novo - Multiplex 33173220 Brunet T et al. (2020)
c.530_531del p.Tyr177LeufsTer3 frameshift_variant De novo - - 28135719 et al. (2017)
c.589-4_591del - splice_site_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.1347C>A p.Tyr449Ter stop_gained De novo - Multiplex 33173220 Brunet T et al. (2020)
c.1425G>T p.Lys475Asn missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1532A>G p.His511Arg missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1310A>C p.Asn437Thr missense_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.1370T>C p.Leu457Pro missense_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.566dup p.Tyr189Ter frameshift_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.1135+2_1135+4del - splice_site_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.1373G>T p.Arg458Leu missense_variant De novo - Multiplex 33173220 Brunet T et al. (2020)
c.1382-1G>A - splice_site_variant Familial Maternal Simplex 33173220 Brunet T et al. (2020)
c.1362_1364del p.Gln454del inframe_deletion De novo - Simplex 33173220 Brunet T et al. (2020)
c.590_593del p.Leu197Ter frameshift_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.766G>A p.Glu256Lys missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.590_593del p.Leu197Ter frameshift_variant Unknown - Multiplex 33173220 Brunet T et al. (2020)
c.1319dup p.Gly441ArgfsTer2 frameshift_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.1146del p.Lys383SerfsTer22 frameshift_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.808_809del p.Pro270ValfsTer8 frameshift_variant Unknown - Multiplex 33173220 Brunet T et al. (2020)
c.973_974del p.Gln326AlafsTer5 frameshift_variant De novo - Multiplex 33173220 Brunet T et al. (2020)
c.1089_1105dup p.Met369ArgfsTer30 frameshift_variant De novo - Simplex 33173220 Brunet T et al. (2020)
c.1168_1169del p.Lys390GlufsTer6 frameshift_variant Unknown Not maternal Multiplex 33173220 Brunet T 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 0.4420628303629

Ranking 17871/25841 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 0.94564687437939

Ranking 2757/18225 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 0.92358839484457

Ranking 9809/18665 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 0.13356092772406

Ranking 5484/20870 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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