Early onset or syndromic epilepsy

Gene: ACTL6B

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

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.

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

• 31031012
• 30656450
• 26539891
• 27171548
• 30237576