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De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome
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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776155/ https://www.ncbi.nlm.nih.gov/pubmed/35054877 http://dx.doi.org/10.3390/ijms23020692 |
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author | 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 |
author_facet | 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 |
author_sort | Dawidziuk, Mateusz |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8776155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87761552022-01-21 De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome 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 Int J Mol Sci Case Report 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. MDPI 2022-01-08 /pmc/articles/PMC8776155/ /pubmed/35054877 http://dx.doi.org/10.3390/ijms23020692 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Case Report 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 De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome |
title | De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome |
title_full | De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome |
title_fullStr | De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome |
title_full_unstemmed | De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome |
title_short | De Novo ACTG1 Variant Expands the Phenotype and Genotype of Partial Deafness and Baraitser–Winter Syndrome |
title_sort | de novo actg1 variant expands the phenotype and genotype of partial deafness and baraitser–winter syndrome |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776155/ https://www.ncbi.nlm.nih.gov/pubmed/35054877 http://dx.doi.org/10.3390/ijms23020692 |
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