[Clinical and genetic analysis of a patient with Alström syndrome presenting with paroxysmal palpitations]

To investigate the clinical features and genetic etiology of a patient with Alström syndrome (ALMS) who presented with paroxysmal palpitations.

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).

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.

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.