Abstract
Actin molecules are fundamental for embryonic structural and functional differentiation; γ-actin is specifically required for the maintenance and function of cytoskeletal structures in the ear, resulting in hearing. Baraitser–Winter Syndrome (B-WS, OMIM #243310, #614583) is a rare, multiple-anomaly genetic disorder caused by mutations in either cytoplasmically expressed actin gene, ACTB (β-actin) or ACTG1 (γ-actin). The resulting actinopathies cause characteristic cerebrofrontofacial and developmental traits, including progressive sensorineural deafness. Both ACTG1-related non-syndromic A20/A26 deafness and B-WS diagnoses are characterized by hypervariable penetrance in phenotype. Here, we identify a 28th patient worldwide carrying a mutated γ-actin ACTG1 allele, with mildly manifested cerebrofrontofacial B-WS traits, hypervariable penetrance of developmental traits and sensorineural hearing loss. This patient also displays brachycephaly and a complete absence of speech faculty, previously unreported for ACTG1-related B-WS or DFNA20/26 deafness, representing phenotypic expansion. The patient’s exome sequence analyses (ES) confirms a de novo ACTG1 variant previously unlinked to the pathology. Additional microarray analysis uncover no further mutational basis for dual molecular diagnosis in our patient. We conclude that γ-actin c.542C > T, p.Ala181Val is a dominant pathogenic variant, associated with mildly manifested facial and cerebral traits typical of B-WS, hypervariable penetrance of developmental traits and sensorineural deafness. We further posit and present argument and evidence suggesting ACTG1-related non-syndromic DFNA20/A26 deafness is a manifestation of undiagnosed ACTG1-related B-WS.
Highlights
IntroductionActin isoforms β and γ are identical except for four amino acid substitutions within the first 10 N-terminal residues
Nuchal translucency at the 95th percentile and a higher risk of trisomy 21 was determined by a non-invasive test (PAPP-A), and a cell-free fetal DNA test was performed
Facial and developmental traits which together are clinically typical for B-WS [8]
Summary
Actin isoforms β and γ are identical except for four amino acid substitutions within the first 10 N-terminal residues. Both isoforms are vital to embryonic differentiation and interact in some tissues, with each having hundreds of first-level interactions with other cellular molecules [1]. These forms have different specific expression patterns and are involved in multiple, largely separate processes, with little functional redundancy [1,2]. Γ-Actin expression predominates in the auditory hair cells [3] and is required for the formation and maintenance of the structures involved in the mechanotransduction of sound waves to electrical signals which are relayed to the brain as hearing [4–7]. Consistent with differential expression patterns, the accumulated data support phenotype–genotype correlation for B-WS-associated mutations in ACTG1 versus ACTB
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