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Whole‐genome sequencing analysis of Japanese autism spectrum disorder trios.

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Title: Whole‐genome sequencing analysis of Japanese autism spectrum disorder trios.
Authors: Furukawa, Sawako (AUTHOR), Kushima, Itaru (AUTHOR), Kato, Hidekazu (AUTHOR), Kimura, Hiroki (AUTHOR), Nawa, Yoshihiro (AUTHOR), Aleksic, Branko (AUTHOR), Banno, Masahiro (AUTHOR), Yamamoto, Maeri (AUTHOR), Uematsu, Mariko (AUTHOR), Nagasaki, Yukako (AUTHOR), Ogi, Tomoo (AUTHOR), Ozaki, Norio (AUTHOR), Ikeda, Masashi (AUTHOR)
Source: Psychiatry & Clinical Neurosciences. Mar2025, Vol. 79 Issue 3, p87-97. 11p.
Subjects: Autism spectrum disorders, Whole genome sequencing, Phenotypes, Genetic variation, Genetic mutation, Japanese people, Neural development
Abstract: Aim: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole‐genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. Methods: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single‐nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). Results: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen‐2, and Constraint >1) showed associations with regulation of growth and ATP‐dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. Conclusion: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology. [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.)
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  Label: Title
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  Data: Whole‐genome sequencing analysis of Japanese autism spectrum disorder trios.
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  Data: <searchLink fieldCode="AR" term="%22Furukawa%2C+Sawako%22">Furukawa, Sawako</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kushima%2C+Itaru%22">Kushima, Itaru</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kato%2C+Hidekazu%22">Kato, Hidekazu</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kimura%2C+Hiroki%22">Kimura, Hiroki</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nawa%2C+Yoshihiro%22">Nawa, Yoshihiro</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Aleksic%2C+Branko%22">Aleksic, Branko</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Banno%2C+Masahiro%22">Banno, Masahiro</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yamamoto%2C+Maeri%22">Yamamoto, Maeri</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Uematsu%2C+Mariko%22">Uematsu, Mariko</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nagasaki%2C+Yukako%22">Nagasaki, Yukako</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ogi%2C+Tomoo%22">Ogi, Tomoo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ozaki%2C+Norio%22">Ozaki, Norio</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ikeda%2C+Masashi%22">Ikeda, Masashi</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Psychiatry+%26+Clinical+Neurosciences%22">Psychiatry & Clinical Neurosciences</searchLink>. Mar2025, Vol. 79 Issue 3, p87-97. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Autism+spectrum+disorders%22">Autism spectrum disorders</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="%22Genetic+variation%22">Genetic variation</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+mutation%22">Genetic mutation</searchLink><br /><searchLink fieldCode="DE" term="%22Japanese+people%22">Japanese people</searchLink><br /><searchLink fieldCode="DE" term="%22Neural+development%22">Neural development</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Aim: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole‐genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. Methods: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single‐nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). Results: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen‐2, and Constraint >1) showed associations with regulation of growth and ATP‐dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. Conclusion: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  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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              Text: Mar2025
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