Further delineation of putative ACTB loss‐of‐function variants: A 4‐patient series

Abstract

ACTB encodes β‐cytoplasmic actin, an essential component of the cytoskeleton. Based on chromosome 7p22.1 deletions that include the ACTB locus and on rare truncating ACTB variants, a phenotype resulting from ACTB haploinsufficiency was recently proposed. We report putative ACTB loss‐of‐function variants in four patients. To the best of our knowledge, we report the first 7p22.1 microdeletion confined to ACTB and the second ACTB frameshifting mutation that predicts mRNA decay. A de‐novo ACTB p.(Gly302Ala) mutation affects β‐cytoplasmic actin distribution. All four patients share a facial gestalt that is distinct from that of individuals with dominant‐negative ACTB variants in Baraitser‐Winter cerebrofrontofacial syndrome. Two of our patients had strikingly thin and sparse scalp hair. One patient had sagittal craniosynostosis and hypospadias. All three affected male children have attention deficits and mild global developmental delay. Mild intellectual disability was present in only one patient. Heterozygous ACTB deletion can allow for normal psychomotor function.

Identification of a De Novo Heterozygous Missense ACTB Variant in Baraitser–Winter Cerebrofrontofacial Syndrome

“…In addition, we found that the expressions of ACTB mRNA and protein were not significantly altered in patients compared with normal controls. This is consistent with the previously reported p.Arg183Trp ( Procaccio et al, 2006 ), p.Arg196His ( Rivière et al, 2012 ), and p.Gly302Ala ( Baumann et al, 2020 ) variants. Thus, we infer that the variant caused the disorder by gain‐of‐function or dominant‐negative mechanisms ( Rivière et al, 2012 ; Di Donato et al, 2014 ; Verloes et al, 2015 ; Baumann et al, 2020 ).…”

“…This is consistent with the previously reported p.Arg183Trp ( Procaccio et al, 2006 ), p.Arg196His ( Rivière et al, 2012 ), and p.Gly302Ala ( Baumann et al, 2020 ) variants. Thus, we infer that the variant caused the disorder by gain‐of‐function or dominant‐negative mechanisms ( Rivière et al, 2012 ; Di Donato et al, 2014 ; Verloes et al, 2015 ; Baumann et al, 2020 ). The correlation between ACTB genotype and phenotype, and the underlying pathogenesis needs to be further determined.…”

“…BWCFF is a very rare genetic disease associated with ACTB variants. In previous case reports, the phenotype of each patient was heterogeneous with different genetic variants, which posed some challenges for clinical diagnosis ( Rivière et al, 2012 ; Johnston et al, 2013 ; Di Donato et al, 2014 ; Verloes et al, 2015 ; Yates et al, 2017 ; Latham et al, 2018 ; Sandestig et al, 2018 ; Sun et al, 2018 ; Baumann et al, 2020 ; Chacon-Camacho et al, 2020 ; Hampshire et al, 2020 ). In this study, the patient showed distinct BWCFF facial and neurodevelopmental anomalies and ocular coloboma.…”

“…Both of them purportedly involve a condition of BWCFF and interpretated as likely pathogenic or pathogenic, but those submitters did not provide more detailed information. Some cases with ACTB gene alteration but without BWCFF phenotype have been recently described ( Cuvertino et al, 2017 ; Latham et al, 2018 ; Baumann et al, 2020 ). The cohort of patients generally carried deletion, frameshift, and nonsense variants in the ACTB gene, which were considered as loss-of-function variants leading to haploinsufficiency.…”