Intellectual disabilityGene: ACTL6B
Comment on list classification: Updated rating from Red to Green based on recent review by Konstantinos Varvagiannis which provides additional recent cases from PMIDs:31031012,30656450,26539891 and 30237576. Sufficient unrelated cases with a consistent ID/global developmental delay phenotype to support inclusion on the panel. Plus functional studies in human and mouse cells in PMIDs:31031012,17920018.
Created: 16 May 2019, 1:43 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).
Sajan et al., 2017 (PMID:27171548) report a homozygous stoploss variant in ACTL6B: c.1279delT (p.X427D) in an ASD case from the DDD study (PMID:25533962) but no other clinical or EEG data was provided.
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 a 13 year old girl (individual 17-1447) with phenotype global developmental delay, epilepsy vs hyperekplexia, and basal ganglia abnormalities.
Created: 16 May 2019, 1:38 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. They also identified 10 unrelated individuals with de novo heterozygous variants with ID, developmental delay, hypotonia, Rett-like stereotypies (e.g. handwringing), and minor facial dysmorphisms: 9/10 of these individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development.
Created: 16 May 2019, 1:35 p.m.
Comment on mode of inheritance: Most literature report biallelic ACTL6B variants in individuals with developmental delay/intellectual disability but Bell et al., 2019 (PMID:31031012) identify both biallelic and heterozygous variants. Therefore have set MOI to BOTH monoallelic and biallelic.
Created: 16 May 2019, 1:30 p.m.
Comment on mode of pathogenicity: Bell et al., 2019 (PMID:31031012) suggest that biallelic variants are loss-of-function, and heterozygous variants are gain-of-function.
Created: 16 May 2019, 1:29 p.m.
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).
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).
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).
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).
As a result ACTL6B can be considered for upgrade to green (or amber).
Created: 30 Apr 2019, 9:50 a.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Global developmental delay, Intellectual disability, Seizures, Spasticity; Global developmental delay, Intellectual disability, Stereotypic behavior, Abnormality of the face
Variants in this GENE are reported as part of current diagnostic practice
Candidate gene variant found in one ID proband
Created: 31 Oct 2017, 9:57 a.m.
Gene: actl6b has been classified as Green List (High Evidence).
Publications for gene: ACTL6B were set to 26350204
Mode of inheritance for gene: ACTL6B was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mode of pathogenicity for gene: ACTL6B was changed from to None
Phenotypes for gene: ACTL6B were changed from to Global developmental delay; Intellectual disability
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Model of inheritance for gene ACTL6B was set to Unknown Publications for gene ACTL6B was set to ['26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ACTL6B was created by ellenmcdonagh
ACTL6B was added to Intellectual disabilitypanel. Sources: Expert Review Red