Comparisons of Genetic and Clinical Findings in Patients with Syndromic to Non-Syndromic Familial Exudative...

To compare the genetic causes, prevalence, and clinical characteristics of syndromic and non-syndromic familial exudative vitreoretinopathy (FEVR). A total of 281 patients with FEVR who underwent clinical and genetic evaluation at five ophthalmological institutions in Japan between 2010 and 2023 were included. Whole-exome sequencing, Sanger sequencing, or karyotype analysis was performed using blood samples from probands and available family members. Clinical characteristics of FEVR probands were assessed according to the presence or absence of systemic abnormalities. Among the 281 FEVR probands, 42 (15%) had syndromic FEVR and 239 (85%) had non-syndromic FEVR. Syndromic FEVR was more frequently diagnosed during infancy (95% vs. 57%, p < 0.0001) and occurred more often in sporadic cases (69% vs. 50%, p = 0.028). Variants in Norrin/β-catenin signaling genes were less common in syndromic FEVR (29% vs. 54%, p = 0.0026), whereas symmetrical retinal severity was more frequently observed (67% vs. 39%, p = 0.001). Sex distribution did not differ between groups. Pathogenic variants were identified in 71% of syndromic cases, most commonly in KIF11, NDP, CTNNB1, DOCK6, TSPAN12, and LRP5. Syndromic FEVR exhibits distinct and heterogeneous genetic and clinical features compared with non-syndromic FEVR. Genotype-phenotype characterization may enable earlier diagnosis.