De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser-Winter Syndrome

• Published in: International journal of molecular sciences 2022-01, Vol.23 (2), p.692
• Main Authors: Dawidziuk, Mateusz, Kutkowska-Kazmierczak, Anna, Bukowska-Olech, Ewelina, Jurek, Marta, Kalka, Ewa, Guilbride, Dorothy Lys, Furmanek, Mariusz Ireneusz, Bekiesinska-Figatowska, Monika, Bal, Jerzy, Gawlinski, Pawel
• Format: Article
• Language: English
• Subjects: ACTG1 gene; Actin; actinopathy; Actins - genetics; Adult; Age; Algorithms; Baraitser–Winter syndrome; Base Sequence; Case Report; Cytoskeleton; Deafness; Deafness - complications; Deafness - diagnostic imaging; Deafness - genetics; DNA microarrays; Ears & hearing; Embryos; Facies; Genetic counseling; Genetic disorders; Genotype; Genotype & phenotype; Genotypes; Growth Disorders - complications; Growth Disorders - diagnostic imaging; Growth Disorders - genetics; Hearing aids; Hearing loss; Humans; Hydrocephalus - complications; Hydrocephalus - diagnostic imaging; Hydrocephalus - genetics; Intellectual disabilities; Magnetic Resonance Imaging; Mental Retardation, X-Linked - complications; Mental Retardation, X-Linked - diagnostic imaging; Mental Retardation, X-Linked - genetics; Microcephaly; Mutation; Mutation - genetics; Obesity - complications; Obesity - diagnostic imaging; Obesity - genetics; partial deafness; Pedigree; Phenotype; Phenotypes; Structure-function relationships; Ultrasonic imaging
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23020692

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, (β-actin) or (γ-actin). The resulting actinopathies cause characteristic cerebrofrontofacial and developmental traits, including progressive sensorineural deafness. Both -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 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 -related B-WS or DFNA20/26 deafness, representing phenotypic expansion. The patient's exome sequence analyses (ES) confirms a de novo 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 -related non-syndromic DFNA20/A26 deafness is a manifestation of undiagnosed -related B-WS.