Alström syndrome: a cross-sectional and follow-up study of 127 patients in China, highlighting genetic variant spectrum and cardiac features.

BACKGROUND

Alström syndrome (ALMS) is a rare autosomal recessive multisystem disorder caused by biallelic pathogenic variants in the ALMS1 gene, characterized by progressive cone-rod dystrophy, early-onset obesity, cardiomyopathy, and multiorgan dysfunction. Despite its clinical significance, comprehensive and population-based studies of ALMS remain limited worldwide, particularly in Asian populations.

METHODS

This cross-sectional and follow-up study enrolled 127 genetically confirmed Chinese ALMS patients (aged 1.0-35.1 years). Whole-exome sequencing (WES) identified ALMS1 variants, and echocardiography evaluated cardiac phenotypes. Retrospective analysis tracked LVEF changes in 11 infantile cardiomyopathy cases.

RESULTS

A total of 132 distinct ALMS1 variants (254 alleles) were identified, including 64 novel variants. Truncating mutations predominated (nonsense: 46.9%, frameshift: 45.3%), with recurrent variants c.10,825 C > T (7.9%), c.2090 C > A (5.5%), and c.10831_10832delAG (4.7%). Clinical manifestations included universal visual impairment (100%, 112/112), obesity (84.1%, 96/114), hearing loss (70.8%, 51/72), hepatic steatosis (66.7%, 40/60), and cardiac abnormalities (58.2%, 46/79). Echocardiographic analysis of 34 patients revealed exon 16 truncating variants were significantly associated with infantile-onset cardiomyopathy (72.7% vs. 30.4%, p < 0.05). In 11 infantile cardiomyopathy cases, LVEF improved post-treatment, yet progressive cardiac enlargement persisted.

CONCLUSION

This study provides the most comprehensive clinical and genetic characterization of Alström syndrome in a Chinese cohort to date, identifying 64 novel ALMS1 variants and expanding the known mutational spectrum of this rare disorder. The findings reveal the multisystem nature of ALMS, with frequent metabolic, hepatic, and cardiac involvement, and emphasize the importance of early recognition, multidisciplinary monitoring, and lifelong management. Together, these results establish an evidence-based foundation for improving genetic counseling, guiding precision diagnosis, and informing future mechanistic and therapeutic research on ALMS.