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A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes
Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb ph...
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/PMC9778325/ https://www.ncbi.nlm.nih.gov/pubmed/36553628 http://dx.doi.org/10.3390/genes13122361 |
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author | Gaweda-Walerych, Katarzyna Sitek, Emilia J. Borczyk, Małgorzata Narożańska, Ewa Brockhuis, Bogna Korostyński, Michał Schinwelski, Michał Siemiński, Mariusz Sławek, Jarosław Zekanowski, Cezary |
author_facet | Gaweda-Walerych, Katarzyna Sitek, Emilia J. Borczyk, Małgorzata Narożańska, Ewa Brockhuis, Bogna Korostyński, Michał Schinwelski, Michał Siemiński, Mariusz Sławek, Jarosław Zekanowski, Cezary |
author_sort | Gaweda-Walerych, Katarzyna |
collection | PubMed |
description | Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory loss, and right-sided hemispatial neglect. Whole-exome sequencing (WES) identified rare single heterozygous variants in ATP7B (c.3207C>A), SORL1 (c.352G>A), SETX (c.2385_2387delAAA), and FOXP1 (c.1762G>A) genes. The functional analysis revealed that the deletion in the SETX gene changed the splicing pattern, which was accompanied by lower SETX mRNA levels in the patient’s fibroblasts, suggesting loss-of-function as the underlying mechanism. In addition, the patient’s fibroblasts demonstrated altered mitochondrial architecture with decreased connectivity, compared to the control individuals. This is the first association of the CBS-PNFA phenotype with the most common ATP7B pathogenic variant p.H1069Q, previously linked to Wilson’s disease, and early onset Parkinson’s disease. This study expands the complex clinical spectrum related to variants in well-known disease genes, such as ATP7B, SORL1, SETX, and FOXP1, corroborating the hypothesis of oligogenic inheritance. To date, the FOXP1 gene has been linked exclusively to neurodevelopmental speech disorders, while our study highlights its possible relevance for adult-onset progressive apraxia of speech, which guarantees further study. |
format | Online Article Text |
id | pubmed-9778325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97783252022-12-23 A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes Gaweda-Walerych, Katarzyna Sitek, Emilia J. Borczyk, Małgorzata Narożańska, Ewa Brockhuis, Bogna Korostyński, Michał Schinwelski, Michał Siemiński, Mariusz Sławek, Jarosław Zekanowski, Cezary Genes (Basel) Article Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory loss, and right-sided hemispatial neglect. Whole-exome sequencing (WES) identified rare single heterozygous variants in ATP7B (c.3207C>A), SORL1 (c.352G>A), SETX (c.2385_2387delAAA), and FOXP1 (c.1762G>A) genes. The functional analysis revealed that the deletion in the SETX gene changed the splicing pattern, which was accompanied by lower SETX mRNA levels in the patient’s fibroblasts, suggesting loss-of-function as the underlying mechanism. In addition, the patient’s fibroblasts demonstrated altered mitochondrial architecture with decreased connectivity, compared to the control individuals. This is the first association of the CBS-PNFA phenotype with the most common ATP7B pathogenic variant p.H1069Q, previously linked to Wilson’s disease, and early onset Parkinson’s disease. This study expands the complex clinical spectrum related to variants in well-known disease genes, such as ATP7B, SORL1, SETX, and FOXP1, corroborating the hypothesis of oligogenic inheritance. To date, the FOXP1 gene has been linked exclusively to neurodevelopmental speech disorders, while our study highlights its possible relevance for adult-onset progressive apraxia of speech, which guarantees further study. MDPI 2022-12-14 /pmc/articles/PMC9778325/ /pubmed/36553628 http://dx.doi.org/10.3390/genes13122361 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 | Article Gaweda-Walerych, Katarzyna Sitek, Emilia J. Borczyk, Małgorzata Narożańska, Ewa Brockhuis, Bogna Korostyński, Michał Schinwelski, Michał Siemiński, Mariusz Sławek, Jarosław Zekanowski, Cezary A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes |
title | A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes |
title_full | A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes |
title_fullStr | A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes |
title_full_unstemmed | A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes |
title_short | A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes |
title_sort | patient with corticobasal syndrome and progressive non-fluent aphasia (cbs-pnfa), with variants in atp7b, setx, sorl1, and foxp1 genes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778325/ https://www.ncbi.nlm.nih.gov/pubmed/36553628 http://dx.doi.org/10.3390/genes13122361 |
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