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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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