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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...

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