Sun Lei, Wang Yueli, Ren Yanlong, Wu Renhua, Zhang Junqing, Zhou Shu, Li Xiaoyan
Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Key Laboratory of Remodeling-Related Cardiovascular Disease of the Ministry of Education, Beijing 100029, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 Apr 10;42(4):480-485. doi: 10.3760/cma.j.cn511374-20240712-00387.
To explore the genetic basis of a patient suspected for Loeys-Dietz syndrome (LDS).
A adult male patient with aneurysmal dilation of the aortic root identified during the treatment for chronic myeloid leukemia at Anzhen Hospital of Capital Medical University in 2021 was selected as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and his family members and subjected to whole-exome sequencing (WES). Candidate variant was verified by bioinformatic analysis, with a focus on the genes associated with hereditary aortic aneurysms. Candidate variant was validated by Sanger sequencing. The online SpliceAI software was used for the prediction of protein function. The results, combined with information from public databases, were used to classify the pathogenicity of the candidate variant according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Ethics Committee of Beijing Anzhen Hospital (Ethics No. 2023163X).
Imaging analysis revealed that the patient had aneurysmal dilation of the aortic root. Based on his clinical features and past history, a provisional diagnosis of LDS was established. WES revealed that the patient had harbored a heterozygous splice site variant c.206+2T>G in the SMAD3 gene (NM_005902). The variant was not reported in public databases and was predicted to be pathogenic by SpliceAI. Sanger sequencing showed that the variant was also present in the proband's mother, sister, nephew, and daughter, but not in his father. Based on the guidelines from the ACMG, the variant was classified as likely pathogenic (PVS1+PM2_Supporting).
The heterozygous splice site variant c.206+2T>G of the SMAD3 gene probably underlay the disease in this patient. Above discovery has enriched the mutational spectrum of LDS, which may facilitate delineation of the genotype-phenotype correlation and provide a basis for further risk stratification and personalized treatment of LDS.
探究一名疑似洛伊斯-迪茨综合征（LDS）患者的遗传基础。
选取2021年在首都医科大学附属北京安贞医院治疗慢性粒细胞白血病期间确诊为主动脉根部瘤样扩张的一名成年男性患者作为研究对象。回顾性收集该患者的临床资料。采集患者及其家庭成员的外周血样本，进行全外显子组测序（WES）。通过生物信息学分析验证候选变异，重点关注与遗传性主动脉瘤相关的基因。通过桑格测序验证候选变异。使用在线SpliceAI软件预测蛋白质功能。结合公共数据库中的信息，根据美国医学遗传学与基因组学学会（ACMG）的指南对候选变异的致病性进行分类。本研究经北京安贞医院伦理委员会批准（伦理编号：2023163X）。
影像学分析显示该患者存在主动脉根部瘤样扩张。根据其临床特征和既往病史，初步诊断为LDS。WES结果显示，该患者的SMAD3基因（NM_005902）存在杂合剪接位点变异c.206+2T>G。该变异在公共数据库中未被报道，且SpliceAI预测其具有致病性。桑格测序显示，该变异也存在于先证者的母亲、姐姐、侄子和女儿中，但不存在于其父亲中。根据ACMG的指南，该变异被分类为可能致病（PVS1+PM2_Supporting）。
SMAD3基因的杂合剪接位点变异c.206+2T>G可能是该患者疾病的病因。上述发现丰富了LDS的突变谱，可能有助于明确基因型-表型相关性，并为LDS进一步的风险分层和个性化治疗提供依据。
