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Genetic epilepsy syndromes

Gene: ACTL6B

Green List (high evidence)

ACTL6B (actin like 6B)
EnsemblGeneIds (GRCh38): ENSG00000077080
EnsemblGeneIds (GRCh37): ENSG00000077080
OMIM: 612458, Gene2Phenotype
ACTL6B is in 3 panels

3 reviews

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

AR EIEE76. Karaca et al, 2015 (26539891) - 2 sibs,both had seizures - hom missense variant. Maddirevula et al, 2019 (30237576) limited clinical info available - don't mention seizures - hom nonsense variant. Fichera et al, 2019 (30656450) - 2 sibs both had severe refractory seizures - hom nonsense variant. Also an unrelated Patient with refractory seizures who also had twin brother sibs who died and were similarly affected - hom missense variant in proband no DNA available from deceased brothers. Bell et al, 2019 (31031012) - 11 children from 10 unrelated families - all but one had seizures in infancy and the other had seizure onset aged 3 - hom or compound het variants (nonsense, fs, splicing and missense), some functional work done. Yuksel et al, 2019 - highly consanguineous Turkish family with EIEE - hom in frame intragenic del.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Rebecca Foulger (Genomics England curator)

I don't know

ACTL6B now has a 'confirmed' rating for 'EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE' in the DD panel of Gene2Phenotype (DDG2P update, 18/09/2019), supporting the Green rating of ACTL6B on this panel.
Created: 3 Oct 2019, 12:14 p.m. | Last Modified: 3 Oct 2019, 12:14 p.m.
Panel Version: 1.347
Kept rating as Green based on Green post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:02 a.m. | Last Modified: 9 Sep 2019, 10:02 a.m.
Panel Version: 1.308
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262
Comment on list classification: ACTL6B was added to the panel and rated Green by Konstantinos Varvagiannis. Updated rating from Grey to Green based on literature evidence provided by Konstantinos; although epilepsy is not the primary phenotype, there are sufficient unrelated cases of seizures in patients with biallelic ACTL6B variants for inclusion on the panel (PMIDs:31031012,30656450,26539891 and 30237576).
Created: 16 May 2019, 2:01 p.m.
Maddirevula et al 2019 (PMID:30237576) searched their database on exomes in search of homozygous variants that could be linked to diseases. They identified the homozygous ACTL6B variant NM_016188.4:c.999T>A:p.(Cys333*) in 13 year old girl (individual 17-1447) with phenotype global developmental delay, epilepsy vs hyperekplexia, and basal ganglia abnormalities.
Created: 16 May 2019, 2:01 p.m.
Karaca et al, 2015 (PMID:26539891) report a homozygous variant (NM_016188: c.G893A; p.R298Q) in two siblings BAB6569 and BAB6570 with severe ID, microcephaly, seizures and some autistic behavioral pattern (BAB6570 appears in the text but not table 1).
Created: 16 May 2019, 1:56 p.m.
Fichera et al. (2019, PMID:30656450) report three individuals from 2 families with affected members characterised by early onset drug-resistant epilepsy, severe psychomotor delay, spastic tetraplegia, microcephaly, diffuse cerebral hypomyelination, and brain or cerebellar atrophy. Individuals had distinct homozygous variants in ACTL6B: NM_016188:c.820C>T;p.Gln274* and NM_016188:c.1045G>A;p.Gly349Ser.
Created: 16 May 2019, 1:56 p.m.
Bell et al., 2019 (PMID:31031012) identified 11 individuals (from 10 families) with biallelic variants in ACTL6B and global developmental delay, epileptic encephalopathy, and spasticity. Seizure types include myoclonias, tonic and myoclonic, focal onset progressing to infantile spasms, and Epilepsy was a feature of all 11 patients (Table 1).
Created: 16 May 2019, 1:47 p.m.
Comment on mode of inheritance: Bell et al., 2019 (PMID:31031012) report biallelic and heterozygous variants in ACTL6B with ID/developmental delay. Seizures were reported in all the biallelic patients but infantile spasms and GTCS (generalized tonic-clonic seizure) was reported in only one heterozygous individual (D7). Therefore kept MOI as biallelic.
Created: 16 May 2019, 1:47 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Epilepsy is a typical feature in individuals with biallelic pathogenic ACTL6B variants, though it is uncommon for the dominant phenotype (only a single individual with seizures probably reported).
Intellectual disability is a prominent feature of the ACTL6B-related disorder, whether this is secondary to biallelic mutations (leading to loss-of-function) or monoallelic ones (probably by a gain-of-function mechanism).

Biallelic ACTL6B mutations: Bell et al. (2019 - PMID: 31031012) report on 11 individuals from 10 families with biallelic variants, adding to 3 individuals from 2 families, recently reported in detail by Fichera et al. (2019 - PMID: 30656450). Previous reports by Karaca et al. (1 individual - 2015 - PMID: 26539891), Sajan et al. (1 individual - 2017 - PMID: 27171548), Maddirevula et al. (2019 - PMID: 30237576) are summarized by Fichera et al. Overlapping features include global DD/ID, epileptic encephalopathy and spasticity.

Monoallelic ACTL6B mutations: Bell et al. (2019 - PMID: 31031012) report on 10 individuals with de novo pathogenic variant, namely a recurrent missense one (9/10 - NM_016188.4:c.1027G>A or p.Gly343Arg) as well as a further missense SNV (c.230A>G or p.Asp77Gly) on one occasion. Features included hypotonia, DD and ID, stereotypic movements, and some possibly suggestive features (wide mouth, diastema, bulbous nose).

ACTL6B (also known as BAF53B) encodes a subunit of the neuron-specific chromatin remodeling complex nBAF.

Some ACTL6B-related phenotypic features were somewhat overlapping to those of other "BAFopathies" (notably Nicolaides-Baraitser and Cofin Siris syndrome - eg. DD/ID, seizures in the recessive type, short phalanges in the dominant one) though others (eg. hair or digital abnormalities) were not observed.

Actl6b knock-out mouse neurons show deficits in dendrite development (cited: Wu et al. 2007 - PMID: 17920018). Additional previous studies have shown deficit in dendritic spine and synapse function in Actl6b KO mice, associated with impaired long-term memory and poor survival (cited: Vogel-Ciernia et al. 2013 - PMID: 23525042).

Bell et al. provide evidence for profound deficits in dendrite develpment in engineered knock-out of ACTL6B in wt human neurons, similar to what was observed in 2 individuals with biallelic mutation. The deficits were reversed upon bi-allelic repair to wild-type or exogenous ACTL6B expression. Additional studies suggested alteration of genomic binding of the BAF complex and transcriptional dysregulation of genes, among other involved in dendrite development.

Loss of ACTL6B function probably explains the recessive phenotype, while a gain-of-function effect is presumed for the dominant one (though the exact mechanism is not known).
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ACTL6B is included in gene panels for ID offered by some diagnostic laboratories.
It is part of the DD panel of G2P, associated with "Unspecified Neurodevelopmental Disorder" (monoallelic variants - disease confidence : probable).
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As a result ACTL6B can be considered for inclusion in the current panel as green (or amber).
Sources: Literature
Created: 30 Apr 2019, 9:53 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Spasticity

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Green
Phenotypes
  • Epileptic encephalopathy, early infantile, 76, 618468
  • Global developmental delay
  • Intellectual disability
  • Seizures
  • Spasticity
  • epileptic encephalopathy
OMIM
612458
Clinvar variants
Variants in ACTL6B
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to ACTL6B.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to ACTL6B.

9 Sep 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy to Epileptic encephalopathy, early infantile, 76, 618468; Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy

16 May 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: actl6b has been classified as Green List (High Evidence).

16 May 2019, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability; Seizures; Spasticity to Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy

16 May 2019, Gel status: 0

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: ACTL6B was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal

30 Apr 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: ACTL6B was added gene: ACTL6B was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ACTL6B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACTL6B were set to 31031012; 30656450; 26539891; 27171548; 30237576 Phenotypes for gene: ACTL6B were set to Global developmental delay; Intellectual disability; Seizures; Spasticity Penetrance for gene: ACTL6B were set to Complete Review for gene: ACTL6B was set to GREEN