ATR-X, an acronym for alpha thalassemia and mental retardation X-linked, syndrome is a congenital condition predominantly affecting males, characterized by mild to severe intellectual disability, facial, skeletal, urogenital, and hematopoietic anomalies. Less common are heart defects, eye anomalies, renal abnormalities, and gastrointestinal dysfunction. ATR-X syndrome is caused by germline variants in the ATRX gene. Until recently, the diagnosis of the ATR-X syndrome had been guided by the classical clinical manifestations and confirmed by molecular techniques. However, our new systematic analysis shows that the only clinical sign shared by all affected individuals is intellectual disability, with the other manifestations varying even within the same family. More than 190 different germline ATRX mutations in some 200 patients have been analyzed. With improved and more frequent analysis by molecular technologies, more subtle deletions and insertions have been detected recently. Moreover, emerging technologies reveal non-classic phenotypes of ATR-X syndrome as well as the description of a new clinical feature, the development of osteosarcoma which suggests an increased cancer risk in ATR-X syndrome. This review will focus on the different types of inherited ATRX mutations and their relation to clinical features in the ATR-X syndrome. We will provide an update of the frequency of clinical manifestations, the affected organs, and the genotype–phenotype correlations. Finally, we propose a shift in the diagnosis of ATR-X patients, from a clinical diagnosis to a molecular-based approach. This may assist clinicians in patient management, risk assessment and genetic counseling.

ATR-X 是 α 地中海贫血和智力低下 X 连锁综合征的首字母缩写，是一种主要影响男性的先天性疾病，其特征是轻度至重度智力障碍、面部、骨骼、泌尿生殖系统和造血异常。不太常见的是心脏缺陷、眼睛异常、肾脏异常和胃肠道功能障碍。ATR-X 综合征是由ATRX基因中的种系变异引起的。直到最近，ATR-X 综合征的诊断一直以经典的临床表现为指导，并通过分子技术得到证实。然而，我们新的系统分析表明，所有受影响个体共有的唯一临床症状是智力障碍，其他表现甚至在同一家庭内也有所不同。超过 190 种不同的种系ATRX已经分析了大约 200 名患者的突变。随着分子技术的改进和更频繁的分析，最近检测到了更细微的缺失和插入。此外，新兴技术揭示了 ATR-X 综合征的非经典表型以及对新临床特征的描述，骨肉瘤的发展表明 ATR-X 综合征的癌症风险增加。本次审查将重点关注不同类型的遗传性ATRX突变及其与 ATR-X 综合征临床特征的关系。我们将提供临床表现频率、受影响器官和基因型-表型相关性的更新。最后，我们建议将 ATR-X 患者的诊断从临床诊断转变为基于分子的方法。这可以帮助临床医生进行患者管理、风险评估和遗传咨询。