Genome-wide epigenetic signatures facilitated the variant classi fi cation of the PURA gene and uncovered the pathomechanism of PURA-related neurodevelopmental disorders

被引：1

作者：

Xiao, Bing ^{[1
]}

Dai, Weiqian ^{[1
]}

Zhan, Yongkun ^{[1
]}

Qiu, Wenjuan ^{[1
]}

Zhang, Huiwen ^{[1
]}

Liu, Danping ^{[2
]}

Xu, Na ^{[1
]}

Yu, Yongguo ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Xinhua Hosp, Shanghai Inst Pediat Res, Sch Med,Dept Pediat Endocrinol & Genet Metab, Room 801,Sci & Educ Bldg,Kong Jiang Rd 1665, Shanghai 200092, Peoples R China

[2] Siontech Genom Co, Shanghai, Peoples R China

来源：

GENETICS IN MEDICINE | 2024年 / 26卷 / 08期

基金：

中国国家自然科学基金; 上海市自然科学基金;

关键词：

DNA methylation; Epigenetic signature; Neurodevelopmental disorder; PURA gene; Variants of uncertainsignificance; BRAIN-DEVELOPMENT; DNA;

D O I：

10.1016/j.gim.2024.101167

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose: Rare genetic variants in the PURA gene cause the PURA -related neurodevelopmental disorder (PURA-NDD), characterized by neonatal abnormalities and developmental delay. Using genome-wide DNA methylation analysis on patients with PURA variants, we aim to establish a PURA-NDD-speci fi c methylation pro fi le and provide further insights on the molecular basis of the PURA-NDD. Methods: Twenty three individuals (including 12 unpublished) carrying PURA variants were enrolled. We conducted the Illumina In fi nium EPIC microarray analysis in 17 PURA-NDD individuals. In vitro experiments were performed to examine how PURA variants affect Pur -a expression. Results: Additional phenotypes in 12 newly identi fi ed patients were described in this study. Genome-wide DNA methylation analysis unveiled distinctive methylation pro fi les to PURANDD, and the established classi fi er can reclassify PURA variants of uncertain signi fi cance. Patients bearing PURA hapoloinsuf fi cient and missense variants have comparable DNA methylation pro fi les, and cells expressing these PURA variants showed consistent Pur -a downregulation, suggesting a haploinsuf fi ciency mechanism. Conclusion: Patients with PURA-NDD exhibit a speci fi c episignature, which has potential to aid identi fi cation and diagnosis of PURA-NDD patients and offer implications for further functional investigations. (c) 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

引用

页数：14