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Short tandem repeat expansions in cortical layer‐specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.

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Title: Short tandem repeat expansions in cortical layer‐specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.
Authors: Kim, Jae Hyun (AUTHOR), Koh, In Gyeong (AUTHOR), Lee, Hyeji (AUTHOR), Lee, Gang‐Hee (AUTHOR), Song, Da‐Yea (AUTHOR), Kim, Soo‐Whee (AUTHOR), Kim, Yujin (AUTHOR), Han, Jae Hyun (AUTHOR), Bong, Guiyoung (AUTHOR), Lee, Jeewon (AUTHOR), Byun, Heejung (AUTHOR), Son, Ji Hyun (AUTHOR), Kim, Ye Rim (AUTHOR), Lee, Yoojeong (AUTHOR), Kim, Justine Jaewon (AUTHOR), Park, Jung Woo (AUTHOR), Kim, Il Bin (AUTHOR), Choi, Jung Kyoon (AUTHOR), Jang, Ja‐Hyun (AUTHOR), Trost, Brett (AUTHOR)
Source: Psychiatry & Clinical Neurosciences. Jul2024, Vol. 78 Issue 7, p405-415. 11p.
Subjects: Microsatellite repeats, Autism spectrum disorders, Phenotypic plasticity, Whole genome sequencing, Phenotypes, Gene frequency, Y chromosome
Abstract: Aim: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. Methods: We analyzed WGS data of 634 ASD families and performed genome‐wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD‐associated STR loci. Results: In ASD cases, rare STR expansions predominantly occurred in early cortical layer‐specific genes involved in neurodevelopment, highlighting the cellular specificity of STR‐associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD‐associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non‐carriers. Conclusion: Short tandem repeat expansions in cortical layer‐specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under‐investigated population. [ABSTRACT FROM AUTHOR]
Copyright of Psychiatry & Clinical Neurosciences is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Short tandem repeat expansions in cortical layer‐specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.
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  Data: <searchLink fieldCode="AR" term="%22Kim%2C+Jae+Hyun%22">Kim, Jae Hyun</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Koh%2C+In+Gyeong%22">Koh, In Gyeong</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lee%2C+Hyeji%22">Lee, Hyeji</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lee%2C+Gang‐Hee%22">Lee, Gang‐Hee</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Song%2C+Da‐Yea%22">Song, Da‐Yea</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kim%2C+Soo‐Whee%22">Kim, Soo‐Whee</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kim%2C+Yujin%22">Kim, Yujin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Han%2C+Jae+Hyun%22">Han, Jae Hyun</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Bong%2C+Guiyoung%22">Bong, Guiyoung</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lee%2C+Jeewon%22">Lee, Jeewon</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Byun%2C+Heejung%22">Byun, Heejung</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Son%2C+Ji+Hyun%22">Son, Ji Hyun</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kim%2C+Ye+Rim%22">Kim, Ye Rim</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lee%2C+Yoojeong%22">Lee, Yoojeong</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kim%2C+Justine+Jaewon%22">Kim, Justine Jaewon</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Park%2C+Jung+Woo%22">Park, Jung Woo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kim%2C+Il+Bin%22">Kim, Il Bin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Choi%2C+Jung+Kyoon%22">Choi, Jung Kyoon</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Jang%2C+Ja‐Hyun%22">Jang, Ja‐Hyun</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Trost%2C+Brett%22">Trost, Brett</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Psychiatry+%26+Clinical+Neurosciences%22">Psychiatry & Clinical Neurosciences</searchLink>. Jul2024, Vol. 78 Issue 7, p405-415. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Microsatellite+repeats%22">Microsatellite repeats</searchLink><br /><searchLink fieldCode="DE" term="%22Autism+spectrum+disorders%22">Autism spectrum disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Phenotypic+plasticity%22">Phenotypic plasticity</searchLink><br /><searchLink fieldCode="DE" term="%22Whole+genome+sequencing%22">Whole genome sequencing</searchLink><br /><searchLink fieldCode="DE" term="%22Phenotypes%22">Phenotypes</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+frequency%22">Gene frequency</searchLink><br /><searchLink fieldCode="DE" term="%22Y+chromosome%22">Y chromosome</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Aim: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. Methods: We analyzed WGS data of 634 ASD families and performed genome‐wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD‐associated STR loci. Results: In ASD cases, rare STR expansions predominantly occurred in early cortical layer‐specific genes involved in neurodevelopment, highlighting the cellular specificity of STR‐associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD‐associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non‐carriers. Conclusion: Short tandem repeat expansions in cortical layer‐specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under‐investigated population. [ABSTRACT FROM AUTHOR]
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  Label:
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  Data: <i>Copyright of Psychiatry & Clinical Neurosciences is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/pcn.13676
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        Text: English
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