Human Gene Module / Chromosome 7 / ACTL6B

ACTL6Bactin like 6B

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 14
Rare Variants / Common Variants
35 / 0
Aliases
ACTL6B, ACTL6,  BAF53B,  arpNalpha
Associated Syndromes
Rett syndrome
Chromosome Band
7q22.1
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

Analysis of 135 ASD probands from consanguineous marriages recruited for the Simons Recessive Autism Cohort (SRAC) in Wenderski et al., 2000 identified six families with segregating loss-of-function variants in ACTL6B; when considering all coding genes, ACTL6B showed genome-wide significance for variants in the SRAC. In the same report, Actl6b knockout mice on two genetic backgrounds displayed ASD-associated behaviors, including social and memory impairments, repetitive behaviors, hyperactivity, and hypoplasia of the corpus callosum. Bell et al., 2019 had previously demonstrated that individuals harboring biallelic mutations in the ACTL6B gene presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies such as handwringing, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Homozygous variants in the ACTL6B gene had previously been identified in three individuals from two families presenting with severe developmental and epileptic encephalopathy in Fichera et al., 2019, as well as in two siblings presenting with intellectual disability, seizures, and autistic behaviors (Karaca et al., 2015) and a female patient diagnosed with atypical Rett syndrome (Sajan et al., 2017). A postzygotic mosaic coding-synonymous variant that was predicted to create a new exonic splicing site in the ACTL6B gene was observed in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Molecular Function

The protein encoded by this gene is a member of a family of actin-related proteins (ARPs) which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene encodes a subunit of the BAF (BRG1/brm-associated factor) complex in mammals, which is functionally related to SWI/SNF complex in S. cerevisiae and Drosophila; the latter is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. This subunit may be involved in the regulation of genes by structural modulation of their chromatin, specifically in the brain.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ACTL6B (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease Karaca E , et al. (2015) No Autistic behavior, microcephaly
2 Support Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2 Sajan SA , et al. (2016) No -
3 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
4 Support Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy Fichera M , et al. (2019) No -
5 Primary Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons Bell S , et al. (2019) No Epilepsy/seizures, ASD or autistic features
6 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
7 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No Hypertonia, GERD
8 Support Pathogenic homozygous variations in ACTL6B cause DECAM syndrome: Developmental delay, Epileptic encephalopathy, Cerebral Atrophy, and abnormal Myelination Yksel Z , et al. (2019) No -
9 Recent Recommendation Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism Wenderski W et al. (2020) Yes DD, ID, epilepsy/seizures
10 Support - Li D et al. (2022) Yes -
11 Support - Krgovic D et al. (2022) Yes ID
12 Support - Levchenko O et al. (2022) No Epilepsy/seizures
13 Support - Zhou X et al. (2022) Yes -
14 Recent Recommendation - Pollina EA et al. (2023) No -
Rare Variants   (35)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.694C>A p.Pro232Thr missense_variant Unknown - - 34968013 Li D et al. (2022)
c.230A>G p.Asp77Gly missense_variant De novo - - 31031012 Bell S , et al. (2019)
c.1027G>A p.Gly343Arg missense_variant De novo - - 31031012 Bell S , et al. (2019)
c.669+1G>A - splice_site_variant Familial - Simplex 31031012 Bell S , et al. (2019)
c.694C>A p.Pro232Thr missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.556C>T p.Gln186Ter stop_gained Familial - Simplex 31031012 Bell S , et al. (2019)
c.724C>T p.Gln242Ter stop_gained Familial - Simplex 31031012 Bell S , et al. (2019)
c.740G>A p.Trp247Ter stop_gained Familial - Simplex 31031012 Bell S , et al. (2019)
c.852C>G p.Tyr284Ter stop_gained Familial - Simplex 31031012 Bell S , et al. (2019)
c.1231C>T p.Gln411Ter stop_gained Familial - Simplex 31031012 Bell S , et al. (2019)
c.1275C>A p.Cys425Ter stop_gained Familial - Multiplex 31031012 Bell S , et al. (2019)
c.930C>T p.Asn310%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.389G>A p.Arg130Gln missense_variant Familial - Simplex 31031012 Bell S , et al. (2019)
c.617T>C p.Leu206Pro missense_variant Familial - Simplex 31031012 Bell S , et al. (2019)
c.360C>T p.Ser120= synonymous_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.289C>T p.Arg97Ter stop_gained Familial Both parents Simplex 31031012 Bell S , et al. (2019)
c.695del p.Pro232GlnfsTer24 frameshift_variant Familial - Multiplex 31031012 Bell S , et al. (2019)
c.820C>T p.Gln274Ter stop_gained Familial Both parents Multiplex 30656450 Fichera M , et al. (2019)
c.892C>T p.Arg298Ter stop_gained Familial Both parents Multiplex 32312822 Wenderski W et al. (2020)
c.1045G>A p.Gly349Ser missense_variant Familial Both parents Multiplex 31031012 Bell S , et al. (2019)
c.441_443del p.Phe147del inframe_deletion Familial Both parents Unknown 31031012 Bell S , et al. (2019)
c.893G>A p.Arg298Gln missense_variant Familial Both parents Multiplex 26539891 Karaca E , et al. (2015)
c.1249G>T p.Gly417Trp missense_variant Familial Both parents Simplex 32312822 Wenderski W et al. (2020)
c.1045G>A p.Gly349Ser missense_variant Familial Both parents Multiplex 30656450 Fichera M , et al. (2019)
c.460C>T p.Leu154Phe missense_variant Familial Both parents Multiplex 32312822 Wenderski W et al. (2020)
c.523A>C p.Thr175Pro missense_variant Familial Both parents Multiplex 32312822 Wenderski W et al. (2020)
c.554T>C p.Leu185Pro missense_variant Familial Both parents Multiplex 35887114 Levchenko O et al. (2022)
c.1177G>A p.Gly393Arg missense_variant Familial Both parents Multiplex 32312822 Wenderski W et al. (2020)
c.1279del p.Ter427AspfsTer34 frameshift_variant Familial Both parents Simplex 31031012 Bell S , et al. (2019)
c.1279del p.Ter427AspfsTer34 frameshift_variant Familial Both parents Multiplex 31031012 Bell S , et al. (2019)
c.1279del p.Ter427AspfsTer34 frameshift_variant Familial Both parents Simplex 27171548 Sajan SA , et al. (2016)
c.465del p.Ala156ProfsTer64 frameshift_variant Familial Both parents Simplex 32312822 Wenderski W et al. (2020)
c.1027G>A p.Gly343Arg missense_variant Unknown Not maternal Multi-generational 31036916 Lecoquierre F , et al. (2019)
c.1261_1275del p.Val421_Cys425del inframe_deletion Familial Both parents Extended multiplex 31134736 Yksel Z , et al. (2019)
c.999T>A p.Cys333Ter stop_gained Familial Both parents Not simplex (positive family history) 31130284 Monies D , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Bell et al., 2019 demonstrated that individuals harboring biallelic mutations in the ACTL6B gene presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies such as handwringing, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Homozygous variants in the ACTL6B gene had previously been identified in three individuals from two families presenting with severe developmental and epileptic encephalopathy in Fichera et al., 2019, as well as in two siblings presenting with intellectual disability, seizures, and autistic behaviors (Karaca et al., 2015) and a female patient diagnosed with atypical Rett syndrome (Sajan et al., 2017). A postzygotic mosaic coding-synonymous variant that was predicted to create a new exonic splicing site in the ACTL6B gene was observed in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

4/1/2020
S
icon
S

Score remained at S

Description

Bell et al., 2019 demonstrated that individuals harboring biallelic mutations in the ACTL6B gene presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies such as handwringing, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Homozygous variants in the ACTL6B gene had previously been identified in three individuals from two families presenting with severe developmental and epileptic encephalopathy in Fichera et al., 2019, as well as in two siblings presenting with intellectual disability, seizures, and autistic behaviors (Karaca et al., 2015) and a female patient diagnosed with atypical Rett syndrome (Sajan et al., 2017). A postzygotic mosaic coding-synonymous variant that was predicted to create a new exonic splicing site in the ACTL6B gene was observed in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Reports Added
[Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Bell et al., 2019 demonstrated that individuals harboring biallelic mutations in the ACTL6B gene presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies such as handwringing, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Homozygous variants in the ACTL6B gene had previously been identified in three individuals from two families presenting with severe developmental and epileptic encephalopathy in Fichera et al., 2019, as well as in two siblings presenting with intellectual disability, seizures, and autistic behaviors (Karaca et al., 2015) and a female patient diagnosed with atypical Rett syndrome (Sajan et al., 2017). A postzygotic mosaic coding-synonymous variant that was predicted to create a new exonic splicing site in the ACTL6B gene was observed in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.75653407573024

Ranking 32/25841 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 0.98713069486597

Ranking 1917/18225 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 0.9303064247357

Ranking 11394/18665 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 0.23506461212265

Ranking 3688/20870 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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