Dual molecular diagnosis of CEP290 and GLI3 mutations identified in an infant with leber congenital amaurosis and postaxial polydactyly, a Bardet-Biedl syndrome phenocopy

Abstract Background Leber congenital amaurosis (LCA) is one of the earliest-onset and most severe forms of inherited retinal disease, and Bardet-Biedl syndrome (BBS) is a rare non-motile primary ciliopathy with a diverse multi-organ phenotype. To our knowledge, we present the first reported genetically confirmed case of LCA10 co-occurring with isolated postaxial polydactyly type A1 harboring CEP290 and GLI3 mutations, which was initially misdiagnosed as BBS. Case presentation A 6-month-old female infant presented with no visual tracking, nystagmus, and postaxial polydactyly. Targeted gene panel testing identified compound heterozygous pathogenic variants in CEP290, leading to a preliminary diagnosis of BBS. Over a 6-year follow-up, the patient developed progressive pigmentary retinopathy with non-recordable electroretinography but did not develop any other systemic features of BBS. A critical, previously overlooked family history of polydactyly in the father prompted further investigation. Whole-exome sequencing revealed an additional likely pathogenic variant in the GLI3 gene, which was paternally inherited and responsible for the isolated polydactyly. The ocular phenotype was definitively attributed to the CEP290 mutations. A final diagnosis of LCA Type 10 (LCA10) with postaxial polydactyly type A1 was established. Conclusions This case illustrates the novel co-occurrence of two distinct genetic disorders: CEP290-associated LCA10 and GLI3-associated isolated polydactyly. The initial diagnostic challenge underscores the complexity of pediatric inherited retinal diseases and highlights several critical lessons. The importance of longitudinal phenotyping, the necessity of a detailed family history, and the superior diagnostic utility of comprehensive genetic testing like whole-exome sequencing over targeted panels in complex presentations. Accurate differentiation between LCA and syndromic ciliopathies like BBS is crucial for prognostic counseling and management, as LCA10 carries a more favorable systemic prognosis and is now a target for emerging gene therapies.