Submission Details

The actin-like protein 6A (ACTL6A) gene is located on chromosome 3 at 3q26 and encodes BRG1-associated factor A, a widely expressed regulatory subunit of the SWI/SNF chromatin-remodeling complex, which functions in cellular differentiation (Bao et al., 2013, PMID: 23395444). ACTL6A was first reported in relation to a neurodevelopmental disorder with dysmorphic features in 2017 (Marom et al., PMID: 28649782). This disorder is characterized by intellectual disability or developmental delay as well as clinical features that include intrauterine growth retardation and failure to thrive in infancy, facial dysmorphisms, digital and urogenital anomalies, and cardiac defects (PMID 28649782). Five variants (1 frameshift, 1 splice-site, and 3 missense variants) have been reported in six cases across four publications (PMID: 28649782; Pascolini et al. 2020, PMID: 31994175; Chen et al. 2021, PMID: 34906496; Yuan et al. 2021, PMID: 34485408) and are included in this curation. The ACTL6A gene is intolerant to loss-of-function variation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is supported by expression and biochemical function, and rescue in a non-human model data (Braun et al. 2021, PMID: 33602870). Homozygous deletion of the mouse homologue (Actl6a) results in early embryonic lethality (Krasteva et al. 2012, PMID: 23018638), while a conditional knockout mouse model demonstrates stalled cell cycle progression, resulting in cell death and disruption of appropriate neuronal cell differentiation (PMID: 33602870). 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. This definitive classification was approved by the ClinGen Syndromic Disorders GCEP in the meeting on July 21, 2023 (SOP Version 9).