Genomic diversity in functionally relevant genes modifies neurodevelopmental versus neoplastic risks in individuals with germline PTEN variants.

IF 4.8 2区医学 Q1 GENETICS & HEREDITY

NPJ Genomic Medicine Pub Date : 2025-05-20 DOI:10.1038/s41525-025-00495-3

Adriel Y Kim, Lamis Yehia, Charis Eng

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引用次数: 0

Abstract

Individuals with germline PTEN variants (PHTS) have increased risks of the seemingly disparate phenotypes of cancer and neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD). Etiology of the phenotypic variability remains elusive. Here, we hypothesized that decreased genomic diversity, manifested by increased homozygosity, may be one etiology. Comprehensive analyses of 376 PHTS patients of European ancestry revealed significant enrichment of homozygous common variants in genes involved in inflammatory processes in the PHTS-NDD group and in genes involved in differentiation and chromatin structure regulation in the PHTS-ASD group. Pathway analysis revealed pathways germane to NDD/ASD, including neuroinflammation and synaptogenesis. Collapsing analysis of the homozygous variants identified suggestive modifier NDD/ASD genes. In contrast, we found enrichment of homozygous ultra-rare variants in genes modulating cell death in the PHTS-cancer group. Finally, homozygosity burden as a predictor of ASD versus cancer outcomes in our validated prediction model for NDD/ASD performed favorably.

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功能相关基因的基因组多样性改变了种系PTEN变异个体的神经发育与肿瘤风险。

患有种系PTEN变异（PHTS）的个体患癌症和神经发育障碍（NDD）（包括自闭症谱系障碍（ASD））的风险增加。表型变异的病因学仍然难以捉摸。在这里，我们假设基因组多样性的减少，表现为纯合性的增加，可能是一个病因。对376名欧洲血统的PHTS患者的综合分析显示，PHTS- ndd组中参与炎症过程的基因和PHTS- asd组中参与分化和染色质结构调节的基因的纯合常见变异显著富集。通路分析揭示了与NDD/ASD相关的通路，包括神经炎症和突触发生。纯合变异体的崩溃分析鉴定出提示修饰NDD/ASD基因。相比之下，我们发现在phts癌症组中，调节细胞死亡的基因中富集了纯合的超罕见变异。最后，在我们验证的NDD/ASD预测模型中，纯合子负担作为ASD与癌症预后的预测因子表现良好。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.