《生命科学》 2026, 38(1): 59-69

Costello综合征的遗传学研究进展

李若冰¹ , 金介员² , 项 荣² , 程振波^1,*

¹湖南师范大学附属第一医院（湖南省人民医院）检验科，长沙 410005 ²中南大学生命科学学院，长沙 410013

摘　要：

Costello综合征（Costello syndrome，CS）是一种罕见的常染色体显性遗传病，以心脏缺陷、特殊颅面特征、生长发育迟缓、皮肤异常等为主要表型。HRAS是Costello综合征的致病基因，现已报道多种有关HRAS的变异。HRAS基因变异导致HRAS蛋白的GTP酶活性降低或GDP/GTP交换活性增强，使HRAS蛋白持续处于活化状态，从而引起RAS/MAPK信号通路的异常激活，通过影响细胞内信号转导扰乱正常生理功能，进而导致患者出现多系统的异常表现，如心脏肥大、智力障碍、皮肤病变等。Costello综合征的遗传学研究可为遗传咨询、产前诊断乃至精准医疗提供依据。

通讯作者：程振波 , Email:zbcheng88hn@163.com

Genetic research progress on Costello syndrome

LI Ruo-Bing¹ , JIN Jie-Yuan² , XIANG Rong² , CHENG Zhen-Bo^1,*

¹Department of Clinical Laboratory, Hunan Provincial People′s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha 410005, China ²School of Life Sciences, Central South University, Changsha 410013, China

Abstract:

Costello syndrome (CS) is a rare autosomal dominant genetic disorder characterized by cardiac anomalies, distinctive craniofacial features, growth and developmental delays, as well as cutaneous abnormalities. Given the complexity of its clinical presentation and underlying pathogenic mechanisms, advances in genetic and molecular research are essential for deepening our understanding of CS and improving patient outcomes. This review systematically synthesizes recent progress on the genetics of CS from four interconnected perspectives: clinical manifestations, molecular pathogenesis, current diagnostic and therapeutic strategies, and future research directions. By critically integrating existing evidence, we aim to elucidate the core molecular mechanisms driven by dysregulated HRAS signaling and to consolidate both established and emerging genotype-phenotype correlations, which are critical for prognosis and clinical management. The HRAS gene, which encodes a pivotal GTPase in cellular signal transduction, lies at the heart of CS pathogenesis. Through a comprehensive analysis of published HRAS mutation data from CS cases worldwide, this review delineates the mutational spectrum, with emphasis on the predominant p.Gly12Ser variant, its functional consequences, and the associated range of clinical phenotypes. We describe how specific germline missense mutations, predominantly affecting codons 12 or 13, impair GTPase activity or accelerate GDP/GTP exchange, leading to constitutive activation of the HRAS protein. This persistent activation results in hyperactivation of the downstream RAS/MAPK signaling pathway, disrupting fundamental cellular processes such as proliferation, differentiation, and apoptosis, ultimately giving rise to the multisystem features of CS, particularly its hallmark cardiac, neurological, and dermatological manifestations. Beyond cataloging genetic variants, this review critically evaluates the translational implications of these findings for clinical practice. It examines how molecular confirmation through HRAS sequencing has refined diagnostic criteria, underscores the necessity of proactive, multidisciplinary management involving cardiology, neurology, and oncology, and highlights the importance of individualized genetic counseling for affected families. In conclusion, HRAS mutations represent the central molecular drivers of CS, with disease pathogenesis primarily mediated by sustained RAS/MAPK pathway activation. A clear understanding of this genetic basis not only facilitates accurate diagnosis, informed reproductive decision-making, and personalized surveillance but also establishes a robust scientific foundation for advancing prenatal diagnostics and developing targeted therapeutic interventions, including MEK inhibitors, for this complex and heterogeneous disorder.

Communication Author：CHENG Zhen-Bo , Email:zbcheng88hn@163.com