Orphanet Journal of Rare Diseases | Genetic and Cardiac Phenotype Study of Alström Syndrome in the Chinese Population

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This study systematically analyzed the clinical and genetic characteristics of 127 Chinese patients with Alström syndrome, reporting 64 novel ALMS1 pathogenic variants for the first time, and revealing a significant association between exon 16 truncating variants and infantile cardiomyopathy. Long-term echocardiographic follow-up provided preliminary evidence of cardiac functional reversibility, offering important insights for early diagnosis and multidisciplinary management.

 

Literature Overview

This article, titled 'Genetic Variant Spectrum and Cardiac Phenotype Analysis of Alström Syndrome in the Chinese Population', was published in the Orphanet Journal of Rare Diseases. It reviews and summarizes the clinical and genetic features of 127 Chinese ALMS patients. The study identified 64 novel ALMS1 pathogenic variants, expanding the mutational landscape, and through echocardiographic analysis, revealed a significant link between exon 16 truncating variants and infantile cardiomyopathy. In addition, long-term follow-up data emphasized the importance of early recognition and multidisciplinary management.

Background Knowledge

Alström Syndrome (ALMS) is a rare autosomal recessive genetic disorder caused by biallelic pathogenic variants in the ALMS1 gene. Its clinical manifestations are highly heterogeneous, including progressive cone-rod dystrophy, early-onset obesity, cardiomyopathy, and multi-system dysfunction. Although studies based on European populations exist, the genetic variant profile in Asian populations remains unclear. ALMS1 mutations are primarily nonsense or frameshift types, with exons 8, 10, and 16 identified as mutation hotspots. However, the relationship between genotype and phenotype, especially the genetic basis of cardiomyopathy, remains poorly studied. Additionally, the natural course of cardiomyopathy in ALMS and the efficacy of interventions are not well understood. This study fills this gap by presenting the first large-scale clinical and genetic analysis of Chinese ALMS patients, providing critical data for understanding the molecular mechanisms and advancing personalized medicine.

 

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Study Methods and Experimental Design

This cross-sectional and follow-up study included 127 genetically confirmed Chinese ALMS patients (age range: 1.0–35.1 years). All subjects underwent whole-exome sequencing (WES) to identify ALMS1 variants, and cardiac phenotypes were assessed using echocardiography. The study also retrospectively analyzed left ventricular ejection fraction (LVEF) changes in 11 patients with infantile cardiomyopathy.

Key Findings and Insights

• A total of 132 distinct ALMS1 variants (254 alleles) were identified, 64 of which were reported for the first time, with allele frequencies below 0.1%.
• The main mutation types were nonsense (46.9%) and frameshift (45.3%), with mutation hotspots in exons 8, 10, and 16. The most common variant was c.10825 C > T (7.9%).
• All patients exhibited visual impairment (100%), followed by obesity (84.1%), hearing loss (70.8%), hepatic steatosis (66.7%), and cardiac abnormalities (58.2%).
• Echocardiographic analysis showed a significant association between exon 16 truncating variants and infantile cardiomyopathy (72.7% vs. 30.4%, p < 0.05).
• Although LVEF improved after treatment in infantile cardiomyopathy patients, cardiac dilation continued to progress, suggesting that structural cardiac remodeling may not be reversible.
• No significant association was found between exon 16 variants and type 2 diabetes, indicating a possible cardiac-specific effect of this variant.
• This study first reported non-ciliary functions of ALMS1 in diverse systems, such as involvement in endosomal recycling, vesicle trafficking, and insulin signaling, providing new directions for disease mechanism research.

Implications and Future Directions

This study established the largest clinical-genetic cohort of ALMS in China, offering foundational data for early screening, multidisciplinary management, and potential gene therapy. Future studies should focus on in vitro and animal models to validate the pathogenic mechanisms of exon 16 truncating variants and explore targeted intervention strategies.

 

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Conclusion

This study systematically characterized the clinical and genetic variant profiles of Chinese ALMS patients, reporting 64 novel ALMS1 pathogenic variants for the first time. It also revealed a significant link between exon 16 variants and infantile cardiomyopathy. Although LVEF may improve after early treatment, structural cardiac abnormalities continue to progress, suggesting that structural remodeling is a key feature of the disease. The study highlights the necessity of multi-system assessment in early diagnosis and provides a solid foundation for future mechanistic and personalized therapeutic research. These findings have significant implications for genetic counseling, prenatal diagnosis, and patient follow-up management.

 

Yiguo Huang, Libo Wang, Qianwen Zhang, Yu Ding, and Xiumin Wang. Alström syndrome: a cross-sectional and follow-up study of 127 patients in China, highlighting genetic variant spectrum and cardiac features. Orphanet Journal of Rare Diseases.