Article record

位于RAD21结合界面的新型新生STAG1变异与低血糖、反复发热、免疫缺陷及典型黏连蛋白病特征相关

A Novel De Novo STAG1 Variant at the RAD21 Binding Interface Is Associated With Hypoglycemia, Recurrent Fever, Immunodeficiency and Features of Classical Cohesinopathies.

临床研究耳科IF 2.9Q3

文献信息

PMID	42713681
原文	在 PubMed 查看原文 ↗
发表日期	2026
作者	Hafiz Muhammad Jafar Hussain 查看其他 10 位作者 Michael Zimmermann；Stephanie L Safgren；Joseph D Farris；Deepak Panwar；Sarah Allen Thurman；Karthik Muthusamy；Raul Urrutia；Myra J Wick；Filippo Pinto E Vairo；Eric W Klee
作者单位	Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA. 查看其他 9 条单位信息 Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.；Computational Structural Genomics Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.；Data Science Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.；Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, USA.；Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.；Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.；Department of Clinical Genomics, Mayo Clinic, Jacksonville, Florida, USA.；Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.；Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
期刊	Clinical genetics
SCI 分区	Q3
IF	2.9
研究类型	临床研究 · 临床
所属专科	耳科

中文摘要

黏连蛋白复合体由SMC1、SMC3、RAD21和STAG1/STAG2组成，对染色体黏连、DNA修复和转录调控至关重要。黏连蛋白组分的致病性变异会导致黏连蛋白病。黏连蛋白病的典型特征包括发育迟缓（DD）、智力障碍（ID）、喂养困难、肌张力低下、身材矮小、听力损失和畸形特征。在此，我们报告一名5岁男孩，具有典型黏连蛋白病特征，包括DD/ID和喂养困难，以及非典型特征如低血糖、反复发热和免疫缺陷。三联外显子组测序在STAG1基因中鉴定出一个新型新生错义变异，意义未明（NM_005862.3:c.643G>A(p.Val215Ile)）。该变异定位于RAD21相互作用界面，分子动力学（MD）模拟显示其构象变化与在其他患者中报告为可能致病性的STAG1变异相当，支持其可能破坏STAG1-RAD21相互作用界面的有害效应。本病例扩展了STAG1相关黏连蛋白病的表型和分子谱，并增进了我们对疾病机制的理解。

英文摘要

The cohesin complex, composed of SMC1, SMC3, RAD21, and STAG1/STAG2, is essential for chromosome cohesion, DNA repair, and transcriptional regulation. Pathogenic variants in cohesin components cause cohesinopathies. The classical characteristics of cohesinopathies include developmental delay (DD), intellectual disability (ID), feeding difficulties, hypotonia, short stature, hearing loss, and dysmorphic features. Here, we present a 5-year-old boy with classical cohesinopathy features, including DD/ID and feeding difficulties, along with non-classical features such as hypoglycemia, recurrent fever, and immunodeficiency. Trio exome sequencing identified a novel de novo missense variant of uncertain significance (NM_005862.3:c.643G>A(p.Val215Ile)) in the STAG1 gene. The variant localizes to the RAD21 interaction interface, and molecular dynamics (MD) simulations revealed conformational changes comparable to other STAG1 variants reported as likely pathogenic in patients, supporting a deleterious effect which may disrupt the STAG1-RAD21 interaction interface. This case expands the phenotypic and molecular spectrum of STAG1-related cohesinopathy and advances our understanding of the disease mechanism.