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Early onset or syndromic epilepsy v2.503 | ACTL6B | Arina Puzriakova Phenotypes for gene: ACTL6B were changed from Epileptic encephalopathy, early infantile, 76, 618468; Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy to Developmental and epileptic encephalopathy 76, OMIM:618468 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.347 | ACTL6B | Rebecca Foulger commented on gene: ACTL6B: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.331 | ACTL6B | Rebecca Foulger Source Wessex and West Midlands GLH was added to ACTL6B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.330 | ACTL6B | Rebecca Foulger Source NHS GMS was added to ACTL6B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.308 | ACTL6B | Rebecca Foulger commented on gene: ACTL6B: Kept rating as Green based on Green post-Webex review from Helen Lord. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.308 | ACTL6B | Rebecca Foulger 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.262 | ACTL6B | Rebecca Foulger edited their review of gene: ACTL6B: Added comment: 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.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.261 | ACTL6B | Helen Lord reviewed gene: ACTL6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.41 | ACTL6B | Rebecca Foulger Classified gene: ACTL6B as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.41 | ACTL6B | Rebecca Foulger Added comment: 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 variant for inclusion on the panel (PMIDs:31031012,30656450,26539891 and 30237576). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.41 | ACTL6B | Rebecca Foulger Gene: actl6b has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.40 | ACTL6B | Rebecca Foulger commented on gene: ACTL6B: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.40 | ACTL6B | Rebecca Foulger commented on gene: ACTL6B: 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). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.40 | ACTL6B | Rebecca Foulger commented on gene: ACTL6B: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.40 | ACTL6B | Rebecca Foulger Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability; Seizures; Spasticity to Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.39 | ACTL6B | Rebecca Foulger commented on gene: ACTL6B: 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). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.39 | ACTL6B | Rebecca Foulger Added comment: Comment on mode of inheritance: Bell et al., 2019 (PMID:31031012) report biallelic and heterozygous variants in ACTL6BÂ 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.39 | ACTL6B | Rebecca Foulger Mode of inheritance for gene: ACTL6B was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.35 | ACTL6B |
Konstantinos Varvagiannis 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 Added comment: 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). --- 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 inclusion in the current panel as green (or amber). Sources: Literature |