摘要目的:探讨因阵发性心悸就诊的Alstr?m综合征(ALMS)患者的临床特征及遗传学病因。方法:选取2024年4月因阵发性心悸就诊于中国医学科学院阜外医院的1例ALMS女性患者(先证者)作为研究对象。收集先证者临床资料。采集先证者及其父母的外周血样各为4 mL，对先证者血样进行全外显子组测序(WES)，经生物信息学分析筛选候选变异并依据美国医学遗传学和基因组学学会(ACMG)制定的《基因变异解读指南》(以下简称为ACMG指南)进行致病性评估。对先证者及其父母进行Sanger测序验证。明确变异的存在及其遗传来源。本研究通过了中国医学科学院阜外医院伦理审查委员会的批准(批准号：2026-3045)结果:本研究先证者临床表现为阵发性心房扑动、视网膜色素变性、2型糖尿病、甲状腺功能减退等多系统受累。电生理检查证实其存在右心房峡部依赖性心房扑动，进行射频消融治疗后症状缓解。先证者WES结果提示 ALMS1基因中检出c.1734dup和c.9472C>T共计2个杂合变异位点，生物信息学分析结果显示c.1734dup为插入或重复导致的移码变异，对应的ALMS1蛋白水平注释为p.Lys579GlufsTer17；c.9472C>T为单核苷酸替换导致的无义变异，对应的ALMS1蛋白水平注释为p.Gln3158Ter。对 ALMS1基因的这2个杂合变异位点的致病性分析结果显示，上述2个变异可能触发无义介导的mRNA降解，符合功能缺失型变异特征，而且在人群数据库及疾病相关数据库中均未检出。根据ACMG指南，将这2个变异均判定为可能致病变异。Sanger测序验证结果显示，2个变异分别来源于先证者父、母，构成 ALMS1基因的复合杂合变异。根据本研究设定的文献检索策略未见该基因变异组合及心房扑动表型患者相关研究的文献报道。本研究分析先证者临床表现可能机制，并总结本病研究最新进展。 结论:ALMS1基因c.9472C>T和c.1734dup的复合杂合变异为本例先证者的遗传学病因。本研究拓展了Alstr?m综合征的基因型-表型谱，有助于提升临床医师对该病患者遗传特征、致病机制与临床表现的认识，为该病患者的早期识别和规范诊治提供参考依据。

abstractsObjective:To investigate the clinical features and genetic etiology of a patient with Alstr?m syndrome (ALMS) who presented with paroxysmal palpitations.Methods:Clinical data were collected from a 20-year-old female patient who was admitted to Fuwai Hospital, Chinese Academy of Medical Sciences in April 2024. Her medical history was obtained, and physical examination, auxiliary investigations, and laboratory tests were carried out. Peripheral blood samples were collected from the patient and her parents. Whole-exome sequencing (WES) was performed, followed by bioinformatic analysis to identify candidate variants. Pathogenicity assessment was conducted based on the guidelines from American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was subsequently conducted for the patient and her parents to confirm the presence of the variants and determine their parental origin. The study was approved by the Ethics Committee of the institution (Ethics No.: 2026-3045).Results:The patient exhibited multisystem involvement including paroxysmal atrial flutter, retinitis pigmentosa, type 2 diabetes mellitus, and hypothyroidism. Electrophysiological examination confirmed right atrial isthmus-dependent atrial flutter. The patient underwent successful radiofrequency ablation. WES revealed that she has harbored heterozygous c. 9472C>T (p.Lys579GlufsTer17) and c. 1734dup (p.Gln3158Ter) variants of the ALMS1 gene. Bioinformatic analysis suggested that both variants can result in significant alteration in the protein. Pathogenicity analysis showed that both variants were unrecorded in the population and disease-related databases and have loss-of-function effects. Based on the ACMG guidelines, both variants were classified as likely pathogenic. Sanger sequencing confirmed that the two variants were inherited from different parents, constituting compound heterozygous variants. The possible mechanisms underlying the patient′s clinical manifestations and recent advances in ALMS research were also summarized. Conclusion:Compound heterozygous ALMS1 variants c. 9472C>T and c. 1734dup probably underlay the pathogenesis of ALMS in this patient. Above findings have expanded the genotype-phenotype spectrum of ALMS and facilitated understanding of its genetic basis, pathogenic mechanism, and clinical manifestations, thereby promoting early diagnosis and standardized management.