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ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10
Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850–4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., se...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9460507/ https://www.ncbi.nlm.nih.gov/pubmed/36092952 http://dx.doi.org/10.1016/j.xhgg.2022.100137 |
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author | Morato Torres, C. Alejandra Zafar, Faria Tsai, Yu-Chih Vazquez, Jocelyn Palafox Gallagher, Michael D. McLaughlin, Ian Hong, Karl Lai, Jill Lee, Joyce Chirino-Perez, Amanda Romero-Molina, Angel Omar Torres, Francisco Fernandez-Ruiz, Juan Ashizawa, Tetsuo Ziegle, Janet Jiménez Gil, Francisco Javier Schüle, Birgitt |
author_facet | Morato Torres, C. Alejandra Zafar, Faria Tsai, Yu-Chih Vazquez, Jocelyn Palafox Gallagher, Michael D. McLaughlin, Ian Hong, Karl Lai, Jill Lee, Joyce Chirino-Perez, Amanda Romero-Molina, Angel Omar Torres, Francisco Fernandez-Ruiz, Juan Ashizawa, Tetsuo Ziegle, Janet Jiménez Gil, Francisco Javier Schüle, Birgitt |
author_sort | Morato Torres, C. Alejandra |
collection | PubMed |
description | Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850–4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)(n) and mixed (ATTCT)(n)-(ATTCC)(n) expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)(n) expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)(n), are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory. |
format | Online Article Text |
id | pubmed-9460507 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-94605072022-09-10 ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10 Morato Torres, C. Alejandra Zafar, Faria Tsai, Yu-Chih Vazquez, Jocelyn Palafox Gallagher, Michael D. McLaughlin, Ian Hong, Karl Lai, Jill Lee, Joyce Chirino-Perez, Amanda Romero-Molina, Angel Omar Torres, Francisco Fernandez-Ruiz, Juan Ashizawa, Tetsuo Ziegle, Janet Jiménez Gil, Francisco Javier Schüle, Birgitt HGG Adv Article Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850–4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)(n) and mixed (ATTCT)(n)-(ATTCC)(n) expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)(n) expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)(n), are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory. Elsevier 2022-08-15 /pmc/articles/PMC9460507/ /pubmed/36092952 http://dx.doi.org/10.1016/j.xhgg.2022.100137 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Morato Torres, C. Alejandra Zafar, Faria Tsai, Yu-Chih Vazquez, Jocelyn Palafox Gallagher, Michael D. McLaughlin, Ian Hong, Karl Lai, Jill Lee, Joyce Chirino-Perez, Amanda Romero-Molina, Angel Omar Torres, Francisco Fernandez-Ruiz, Juan Ashizawa, Tetsuo Ziegle, Janet Jiménez Gil, Francisco Javier Schüle, Birgitt ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10 |
title | ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10 |
title_full | ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10 |
title_fullStr | ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10 |
title_full_unstemmed | ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10 |
title_short | ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10 |
title_sort | attct and attcc repeat expansions in the atxn10 gene affect disease penetrance of spinocerebellar ataxia type 10 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9460507/ https://www.ncbi.nlm.nih.gov/pubmed/36092952 http://dx.doi.org/10.1016/j.xhgg.2022.100137 |
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