Gene-related retinal detachment in a young Chinese cohort: ACMG/AMP applicability and VUS analysis

To investigate the genetic mutation profiles of gene-related retinal detachment (RD) and evaluate the utility of The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) pathogenicity classification system with emphasis on variants of uncertain significance (VUS) in a young Chinese cohort.

A consecutive cohort of 28 patients under 30y with RD and clinical features suggesting genetic etiology was enrolled between September 2024 and August 2025 at Zhongshan Ophthalmic Center. All patients underwent comprehensive ophthalmic examinations, genetic testing, and surgical repair. Genetic variants were interpreted via the ACMG/AMP criteria.

The cohort consisted of 21 males and 7 females, with a mean age of 15.1±6.71y (ranged: 4–29). The predominant etiologies were Stickler syndrome (10/28, 35.7%), familial exudative vitreoretinopathy (FEVR; 6/28, 21.4%), and Marfan syndrome (4/28, 14.3%). A total of 30 disease-associated variants were identified, among which 60.0% (18/30) were classified as pathogenic/likely pathogenic (P/LP) and 40.0% (12/30) as VUS per ACMG/AMP criteria. The primary factors contributing to VUS classification included high population allele frequency (33.3%), variant novelty (33.3%), and discrepant in silico predictions (25.0%). Patients with P/LP variants exhibited a significantly higher prevalence of high myopia (<-6 D; 93.8% vs 50.0%, P=0.027) and tessellated fundus (87.5% vs 50.0%, P=0.044) compared to those with VUS/not available (NA) variants.

Stickler syndrome, FEVR, and Marfan syndrome are the leading causes of gene-related RD in the Chinese Han cohort. A high VUS rate (40.0%) poses diagnostic challenges, primarily due to population-specific frequency differences, novel variants, and insufficient functional evidence. By integrating clinical history, phenotypic manifestations, and family history, a clear diagnosis can be established in 66.7% of VUS cases. Ethnically tailored genomic databases and expanded multicenter cohorts are needed to improve VUS resolution and enhance the clinical utility of genetic testing in young RD individuals.