Cargando…

Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range

PURPOSE: In some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the vari...

Descripción completa

Detalles Bibliográficos
Autores principales: Findlay Black, Hailey, Wright, Galen E. B., Collins, Jennifer A., Caron, Nicholas, Kay, Chris, Xia, Qingwen, Arning, Larissa, Bijlsma, Emilia K., Squitieri, Ferdinando, Nguyen, Huu Phuc, Hayden, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708297/
https://www.ncbi.nlm.nih.gov/pubmed/32741964
http://dx.doi.org/10.1038/s41436-020-0917-z
_version_ 1783617530966835200
author Findlay Black, Hailey
Wright, Galen E. B.
Collins, Jennifer A.
Caron, Nicholas
Kay, Chris
Xia, Qingwen
Arning, Larissa
Bijlsma, Emilia K.
Squitieri, Ferdinando
Nguyen, Huu Phuc
Hayden, Michael R.
author_facet Findlay Black, Hailey
Wright, Galen E. B.
Collins, Jennifer A.
Caron, Nicholas
Kay, Chris
Xia, Qingwen
Arning, Larissa
Bijlsma, Emilia K.
Squitieri, Ferdinando
Nguyen, Huu Phuc
Hayden, Michael R.
author_sort Findlay Black, Hailey
collection PubMed
description PURPOSE: In some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI’s effect on AOO. METHODS: We developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO. RESULTS: Mean onset for LOI carriers (n = 49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36–39 CAGs). CONCLUSION: The LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36–39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range.
format Online
Article
Text
id pubmed-7708297
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group US
record_format MEDLINE/PubMed
spelling pubmed-77082972020-12-07 Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range Findlay Black, Hailey Wright, Galen E. B. Collins, Jennifer A. Caron, Nicholas Kay, Chris Xia, Qingwen Arning, Larissa Bijlsma, Emilia K. Squitieri, Ferdinando Nguyen, Huu Phuc Hayden, Michael R. Genet Med Brief Communication PURPOSE: In some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI’s effect on AOO. METHODS: We developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO. RESULTS: Mean onset for LOI carriers (n = 49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36–39 CAGs). CONCLUSION: The LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36–39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range. Nature Publishing Group US 2020-08-03 2020 /pmc/articles/PMC7708297/ /pubmed/32741964 http://dx.doi.org/10.1038/s41436-020-0917-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. If you remix, transform, or build upon this article or a part thereof, you must distribute your contributions under the same license as the original. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/.
spellingShingle Brief Communication
Findlay Black, Hailey
Wright, Galen E. B.
Collins, Jennifer A.
Caron, Nicholas
Kay, Chris
Xia, Qingwen
Arning, Larissa
Bijlsma, Emilia K.
Squitieri, Ferdinando
Nguyen, Huu Phuc
Hayden, Michael R.
Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range
title Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range
title_full Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range
title_fullStr Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range
title_full_unstemmed Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range
title_short Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range
title_sort frequency of the loss of caa interruption in the htt cag tract and implications for huntington disease in the reduced penetrance range
topic Brief Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708297/
https://www.ncbi.nlm.nih.gov/pubmed/32741964
http://dx.doi.org/10.1038/s41436-020-0917-z
work_keys_str_mv AT findlayblackhailey frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT wrightgaleneb frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT collinsjennifera frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT caronnicholas frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT kaychris frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT xiaqingwen frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT arninglarissa frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT bijlsmaemiliak frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT squitieriferdinando frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT nguyenhuuphuc frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange
AT haydenmichaelr frequencyofthelossofcaainterruptioninthehttcagtractandimplicationsforhuntingtondiseaseinthereducedpenetrancerange