Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder
Autism spectrum disorder (ASD) is a complex group of clinically heterogeneous neurodevelopmental disorders with unclear etiology and pathogenesis. Genetic studies have identified numerous candidate genetic variants, including de novo mutated ASD-associated genes; however, the function of these de no...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Online |
| Language: | English |
| Published: |
Nature Publishing Group
2016
|
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819764/ |
| id |
pubmed-4819764 |
|---|---|
| recordtype |
oai_dc |
| spelling |
pubmed-48197642016-04-17 Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder Hashimoto, Ryota Nakazawa, Takanobu Tsurusaki, Yoshinori Yasuda, Yuka Nagayasu, Kazuki Matsumura, Kensuke Kawashima, Hitoshi Yamamori, Hidenaga Fujimoto, Michiko Ohi, Kazutaka Umeda-Yano, Satomi Fukunaga, Masaki Fujino, Haruo Kasai, Atsushi Hayata-Takano, Atsuko Shintani, Norihito Takeda, Masatoshi Matsumoto, Naomichi Hashimoto, Hitoshi Original Article Autism spectrum disorder (ASD) is a complex group of clinically heterogeneous neurodevelopmental disorders with unclear etiology and pathogenesis. Genetic studies have identified numerous candidate genetic variants, including de novo mutated ASD-associated genes; however, the function of these de novo mutated genes remains unclear despite extensive bioinformatics resources. Accordingly, it is not easy to assign priorities to numerous candidate ASD-associated genes for further biological analysis. Here we developed a convenient system for identifying an experimental evidence-based annotation of candidate ASD-associated genes. We performed trio-based whole-exome sequencing in 30 sporadic cases of ASD and identified 37 genes with de novo single-nucleotide variations (SNVs). Among them, 5 of those 37 genes, POGZ, PLEKHA4, PCNX, PRKD2 and HERC1, have been previously reported as genes with de novo SNVs in ASD; and consultation with in silico databases showed that only HERC1 might be involved in neural function. To examine whether the identified gene products are involved in neural functions, we performed small hairpin RNA-based assays using neuroblastoma cell lines to assess neurite development. Knockdown of 8 out of the 14 examined genes significantly decreased neurite development (P<0.05, one-way analysis of variance), which was significantly higher than the number expected from gene ontology databases (P=0.010, Fisher's exact test). Our screening system may be valuable for identifying the neural functions of candidate ASD-associated genes for further analysis and a substantial portion of these genes with de novo SNVs might have roles in neuronal systems, although further detailed analysis might eliminate false positive genes from identified candidate ASD genes. Nature Publishing Group 2016-03 2015-11-19 /pmc/articles/PMC4819764/ /pubmed/26582266 http://dx.doi.org/10.1038/jhg.2015.141 Text en Copyright © 2016 The Japan Society of Human Genetics http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Hashimoto, Ryota Nakazawa, Takanobu Tsurusaki, Yoshinori Yasuda, Yuka Nagayasu, Kazuki Matsumura, Kensuke Kawashima, Hitoshi Yamamori, Hidenaga Fujimoto, Michiko Ohi, Kazutaka Umeda-Yano, Satomi Fukunaga, Masaki Fujino, Haruo Kasai, Atsushi Hayata-Takano, Atsuko Shintani, Norihito Takeda, Masatoshi Matsumoto, Naomichi Hashimoto, Hitoshi |
| spellingShingle |
Hashimoto, Ryota Nakazawa, Takanobu Tsurusaki, Yoshinori Yasuda, Yuka Nagayasu, Kazuki Matsumura, Kensuke Kawashima, Hitoshi Yamamori, Hidenaga Fujimoto, Michiko Ohi, Kazutaka Umeda-Yano, Satomi Fukunaga, Masaki Fujino, Haruo Kasai, Atsushi Hayata-Takano, Atsuko Shintani, Norihito Takeda, Masatoshi Matsumoto, Naomichi Hashimoto, Hitoshi Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder |
| author_facet |
Hashimoto, Ryota Nakazawa, Takanobu Tsurusaki, Yoshinori Yasuda, Yuka Nagayasu, Kazuki Matsumura, Kensuke Kawashima, Hitoshi Yamamori, Hidenaga Fujimoto, Michiko Ohi, Kazutaka Umeda-Yano, Satomi Fukunaga, Masaki Fujino, Haruo Kasai, Atsushi Hayata-Takano, Atsuko Shintani, Norihito Takeda, Masatoshi Matsumoto, Naomichi Hashimoto, Hitoshi |
| author_sort |
Hashimoto, Ryota |
| title |
Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder |
| title_short |
Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder |
| title_full |
Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder |
| title_fullStr |
Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder |
| title_full_unstemmed |
Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder |
| title_sort |
whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder |
| description |
Autism spectrum disorder (ASD) is a complex group of clinically heterogeneous neurodevelopmental disorders with unclear etiology and pathogenesis. Genetic studies have identified numerous candidate genetic variants, including de novo mutated ASD-associated genes; however, the function of these de novo mutated genes remains unclear despite extensive bioinformatics resources. Accordingly, it is not easy to assign priorities to numerous candidate ASD-associated genes for further biological analysis. Here we developed a convenient system for identifying an experimental evidence-based annotation of candidate ASD-associated genes. We performed trio-based whole-exome sequencing in 30 sporadic cases of ASD and identified 37 genes with de novo single-nucleotide variations (SNVs). Among them, 5 of those 37 genes, POGZ, PLEKHA4, PCNX, PRKD2 and HERC1, have been previously reported as genes with de novo SNVs in ASD; and consultation with in silico databases showed that only HERC1 might be involved in neural function. To examine whether the identified gene products are involved in neural functions, we performed small hairpin RNA-based assays using neuroblastoma cell lines to assess neurite development. Knockdown of 8 out of the 14 examined genes significantly decreased neurite development (P<0.05, one-way analysis of variance), which was significantly higher than the number expected from gene ontology databases (P=0.010, Fisher's exact test). Our screening system may be valuable for identifying the neural functions of candidate ASD-associated genes for further analysis and a substantial portion of these genes with de novo SNVs might have roles in neuronal systems, although further detailed analysis might eliminate false positive genes from identified candidate ASD genes. |
| publisher |
Nature Publishing Group |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819764/ |
| _version_ |
1613561804410060800 |