ACTB

Inheritance Pattern: AD

Disease ID:MONDO:0009470

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0011823

Submitter: Illumina

The ACTB gene was first reported in relation to autosomal dominant juvenile onset dystonia in 2006 (16685646: Procaccio et al. 2006). Evidence supporting this gene-disease relationship includes case-level data and experimental data. A single recurrent missense variant in this gene has been reported in five unrelated cases from five reports. At least one case was confirmed as de novo inheritance, with another family showing inheritance of the variant in an affected daughter from her affected mother (16685646: Procaccio et al. 2006; 28487785: Conboy et al. 2017; 27862284: Eggink et al. 2017; 28849312: Zech et al. 2017; 29788902: Skogseid et al. 2018). The mechanism for disease is unknown. Of note, this gene has also been implicated in Baraitser–Winter Cerebrofrontofacial syndrome and ACTB-related syndromic thrombocytopenia. These will be assessed separately. This gene-disease relationship is supported by a knockout mouse model which recapitulates the progressive sensorineural hearing loss phenotype observed patients. Beta actin plays a specific role in maintenance of sterocilia of the inner ear, loss of beta actin in the knockout mice specifically leads to the degeneration of the stereocilia of the outer hair cells (30012594: Patrinostro et al. 2018). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

Inheritance Pattern: AD

Disease ID:MONDO:0017579

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0009470

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011823

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0009470

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011823

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0100433

Submitter: ClinGen

*ACTB* was first reported in relation to *ACTB*-associated syndromic thrombocytopenia (ACTB-AST) in 2018 (Latham et al., PMID:30315159). The ACTB gene encodes beta-actin which plays a role in cellular processes, including cell migration and division, cell shape, and the regulation of gene expression. *ACTB*-associated syndromic thrombocytopenia is an autosomal dominant syndromic disorder characterized by developmental delay, mild intellectual disability, microcephaly, facial abnormalities, and thrombocytopenia with platelet anisotropy and enlarged platelets. *ACTB* is also associated with Baraitser-Winter syndrome 1, Becker nevus syndrome, developmental malformation deafness/dystonia syndrome, and intellectual disability. *ACTB*-AST is curated as a unique disease, and to date, only variants in the 5th and 6th exon (pen/ultimate exons) of *ACTB* have been implicated in *ACTB*-associated syndromic thrombocytopenia. Evidence supporting this gene-disease curation includes case level data and experimental data. Summary of Case Level Data (5.8 points): Eight unique variants (missense, amino acid deletions, and frameshift) have been reported in humans, including instances of de novo variation. Variants in this gene have been reported in at least 8 probands in 5 publications (Latham et al., 2018 PMID: 30315159; Nunoi et al., 1999 PMID: 10411937; Fouassier et al., 2023 PMID: 36564926; Atmar et al., 2022 PMID: 35572556; Marconi et al., 2023 PMID: 36519321). Variants in this gene segregated with disease in 2 additional family members. Summary of Experimental Evidence (2.5 points): The gene-disease relationship is supported by expression, biochemical function, and functional alteration in patient cell experiments (Latham et al., PMID:30315159). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Hemostasis and Thrombosis (H/T) Gene Curation Expert Panel on 11/24/2021. It was reevaluated on 05/25/2022 and additional evidence was added (Greve et al., 2022 PMID: 35313204). On June 3rd, 2024, the gene-disease classification was re-evaluated again, and although additional scoreable genetic evidence has emerged, the classification did not change. Of note, there are two published cases in which variants in the 4th exon of *ACTB* are seen in individuals with a phenotype that partially overlaps the phenotype seen in individuals with *ACTB*-AST. These variants are included in the curation, but are not scored at this time (Sandestig et al., 2019 PMID: 30733661; Megy et al., 2021 PMID: 34355501).

Inheritance Pattern: AD

Disease ID:MONDO:0100433

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0017579

Submitter: ClinGen

De novo variants in ACTB were first reported individuals with autosomal dominant Baraitser-Winter syndrome (BWS) in 2012 (Rivière et al., PMID 22366783). BWS (initially described in 1988 by Baraitser and Winter) is characterized by distinct facial features (the combination of congenital ptosis, high-arched eyebrows, hypertelorism, ocular coloboma) and cerebral malformations ( anterior-predominant lissencephaly, microcephaly) with other abnormalities. Phenotypic variability has been reported. The mechanism of pathogenicity is known to be de novo gain-of-function. Interestingly, loss -of -function variants in this gene have been purported to cause a different neurodevelopmental disorder (described in PMID: 29220674); these variants were not considered as part of this curation. At least eleven missense variants have been reported in 18 probands with BWS across six publications (PMIDs: 23756437, 23649928, 22366783, 29388391, 25052316, 16685646). This gene-disease relationship is also supported by a G-actin polymerization assay with yeast (PMID 23649928), in vitro functional assays, and immunofluorescence staining with patient derived lymphoblastoid cell (PMIDs: 22366783, 16685646). In summary, ACTB is definitively associated with autosomal dominant Baraitser-Winter syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This was approved by the ClinGen Brain Malformations GCEP on October 26, 2021.

Inheritance Pattern: AD

Disease ID:MONDO:0011823

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0100433

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0009470

Submitter: PanelApp Australia