罕见的编码变异对神经发育障碍个体小头畸形的贡献。

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Jihoon G Yoon, Hyunsoo Jang, Seungbok Lee, Se Song Jang, Soojin Park, Jaeso Cho, Minji Kim, Jiye Han, Hyounji Yun, Man Jin Kim, Soo Yeon Kim, Woo Joong Kim, Anna Cho, Jin Sook Lee, Murim Choi, Alberto Fernandez-Jaen, Sebastian Silva, Reinaldo Uribe-San-Martín, Christian Cantillano, Noriko Miyake, Byung Chan Lim, Jung Min Ko, Ki Joong Kim, Ki-Jun Yoon, Jong-Hee Chae
{"title":"罕见的编码变异对神经发育障碍个体小头畸形的贡献。","authors":"Jihoon G Yoon, Hyunsoo Jang, Seungbok Lee, Se Song Jang, Soojin Park, Jaeso Cho, Minji Kim, Jiye Han, Hyounji Yun, Man Jin Kim, Soo Yeon Kim, Woo Joong Kim, Anna Cho, Jin Sook Lee, Murim Choi, Alberto Fernandez-Jaen, Sebastian Silva, Reinaldo Uribe-San-Martín, Christian Cantillano, Noriko Miyake, Byung Chan Lim, Jung Min Ko, Ki Joong Kim, Ki-Jun Yoon, Jong-Hee Chae","doi":"10.1186/s13073-025-01513-w","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Microcephaly, characterized by an abnormally small head size, frequently co-occurs with neurodevelopmental disorders (NDDs). While the genetic basis of NDDs has been widely investigated, the contribution of rare coding variants to microcephaly remains poorly understood.</p><p><strong>Methods: </strong>We investigated the relationships between head circumference and rare coding variants in 418 individuals with microcephaly, analyzing data from 1050 exomes (312 trios and 106 proband-only samples). Participants were classified into primary microcephaly (PM) and secondary microcephaly (SM) groups, and their clinical and genetic characteristics were systematically assessed. The functional impact of high-priority candidate genes, RTF1 and ASAP2, was further validated using neural progenitor cells (NPCs) and human forebrain organoid models.</p><p><strong>Results: </strong>Exome sequencing revealed 142 causative and 12 candidate genes associated with microcephaly. Pathway analyses indicated that PM genes are linked to early phases of brain development, whereas SM genes are more associated with later stages of neuronal maturation. In addition, the PM group had a significantly higher proportion of autosomal recessive disorders and exhibited more severe microcephaly than the SM group. Notably, females displayed greater microcephaly severity than males, primarily attributable to differences in the origin of the allele and inheritance patterns on the X chromosome. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 and ASAP2 in brain development.</p><p><strong>Conclusions: </strong>This study sheds light on the complex genetic architecture of microcephaly, emphasizing the impact of rare coding variants on brain development and delineating distinct clinical and molecular profiles underlying PM and SM.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"86"},"PeriodicalIF":10.4000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326769/pdf/","citationCount":"0","resultStr":"{\"title\":\"Contribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders.\",\"authors\":\"Jihoon G Yoon, Hyunsoo Jang, Seungbok Lee, Se Song Jang, Soojin Park, Jaeso Cho, Minji Kim, Jiye Han, Hyounji Yun, Man Jin Kim, Soo Yeon Kim, Woo Joong Kim, Anna Cho, Jin Sook Lee, Murim Choi, Alberto Fernandez-Jaen, Sebastian Silva, Reinaldo Uribe-San-Martín, Christian Cantillano, Noriko Miyake, Byung Chan Lim, Jung Min Ko, Ki Joong Kim, Ki-Jun Yoon, Jong-Hee Chae\",\"doi\":\"10.1186/s13073-025-01513-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Microcephaly, characterized by an abnormally small head size, frequently co-occurs with neurodevelopmental disorders (NDDs). While the genetic basis of NDDs has been widely investigated, the contribution of rare coding variants to microcephaly remains poorly understood.</p><p><strong>Methods: </strong>We investigated the relationships between head circumference and rare coding variants in 418 individuals with microcephaly, analyzing data from 1050 exomes (312 trios and 106 proband-only samples). Participants were classified into primary microcephaly (PM) and secondary microcephaly (SM) groups, and their clinical and genetic characteristics were systematically assessed. The functional impact of high-priority candidate genes, RTF1 and ASAP2, was further validated using neural progenitor cells (NPCs) and human forebrain organoid models.</p><p><strong>Results: </strong>Exome sequencing revealed 142 causative and 12 candidate genes associated with microcephaly. Pathway analyses indicated that PM genes are linked to early phases of brain development, whereas SM genes are more associated with later stages of neuronal maturation. In addition, the PM group had a significantly higher proportion of autosomal recessive disorders and exhibited more severe microcephaly than the SM group. Notably, females displayed greater microcephaly severity than males, primarily attributable to differences in the origin of the allele and inheritance patterns on the X chromosome. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 and ASAP2 in brain development.</p><p><strong>Conclusions: </strong>This study sheds light on the complex genetic architecture of microcephaly, emphasizing the impact of rare coding variants on brain development and delineating distinct clinical and molecular profiles underlying PM and SM.</p>\",\"PeriodicalId\":12645,\"journal\":{\"name\":\"Genome Medicine\",\"volume\":\"17 1\",\"pages\":\"86\"},\"PeriodicalIF\":10.4000,\"publicationDate\":\"2025-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326769/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genome Medicine\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s13073-025-01513-w\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Medicine","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13073-025-01513-w","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

摘要

背景:小头畸形,以异常小的头部尺寸为特征,经常与神经发育障碍(ndd)共同发生。虽然ndd的遗传基础已被广泛研究,但罕见的编码变异对小头畸形的贡献仍然知之甚少。方法:研究了418例小头畸形患者的头围与罕见编码变异之间的关系,分析了来自1050个外显子组(312个三联体和106个纯先证样本)的数据。将参与者分为原发性小头畸形(PM)组和继发性小头畸形(SM)组,系统评估其临床和遗传特征。高优先级候选基因RTF1和ASAP2的功能影响通过神经祖细胞(npc)和人类前脑类器官模型进一步验证。结果:外显子组测序显示142个致病基因和12个候选基因与小头畸形相关。通路分析表明,PM基因与大脑发育的早期阶段有关,而SM基因与神经元成熟的后期阶段有关。此外,PM组的常染色体隐性遗传病比例明显高于SM组,小头畸形也比SM组严重。值得注意的是,女性表现出比男性更严重的小头畸形,这主要归因于X染色体上等位基因的起源和遗传模式的差异。在NPC和脑类器官中使用CRISPR-Cas9敲除的功能实验表明,NPC增殖减少,支持RTF1和ASAP2在大脑发育中的重要作用。结论:本研究揭示了小头畸形的复杂遗传结构,强调了罕见的编码变异对大脑发育的影响,并描绘了PM和SM不同的临床和分子特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Contribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders.

Background: Microcephaly, characterized by an abnormally small head size, frequently co-occurs with neurodevelopmental disorders (NDDs). While the genetic basis of NDDs has been widely investigated, the contribution of rare coding variants to microcephaly remains poorly understood.

Methods: We investigated the relationships between head circumference and rare coding variants in 418 individuals with microcephaly, analyzing data from 1050 exomes (312 trios and 106 proband-only samples). Participants were classified into primary microcephaly (PM) and secondary microcephaly (SM) groups, and their clinical and genetic characteristics were systematically assessed. The functional impact of high-priority candidate genes, RTF1 and ASAP2, was further validated using neural progenitor cells (NPCs) and human forebrain organoid models.

Results: Exome sequencing revealed 142 causative and 12 candidate genes associated with microcephaly. Pathway analyses indicated that PM genes are linked to early phases of brain development, whereas SM genes are more associated with later stages of neuronal maturation. In addition, the PM group had a significantly higher proportion of autosomal recessive disorders and exhibited more severe microcephaly than the SM group. Notably, females displayed greater microcephaly severity than males, primarily attributable to differences in the origin of the allele and inheritance patterns on the X chromosome. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 and ASAP2 in brain development.

Conclusions: This study sheds light on the complex genetic architecture of microcephaly, emphasizing the impact of rare coding variants on brain development and delineating distinct clinical and molecular profiles underlying PM and SM.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信